ArticlePDF Available

Dithymoquinone as a novel inhibitor for 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) to prevent renal failure

Authors:

Abstract and Figures

3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is a major endogenous ligand found in the human serum albumin (HSA) of renal failure patients. It gets accumulated in the HSA and its concentration in sera of patients may reflect the chronicity of renal failure [1-4]. It is considered uremic toxin due to its damaging effect on the renal cells. The high concentrations of CMPF inhibit the binding of other ligands to HSA. Removal of CMPF is difficult through conventional hemodialysis due to its strong binding affinity. We hypothesized that the competitive inhibition may be helpful in removal of CMPF binding to HSA. A compound with higher HSA binding affinity than CMPF could be useful to prevent CMPF from binding so that CMPF could be excreted by the body through the urine. We studied an active compound dihydrothymoquinone/ dithymoquinone (DTQ) found in black cumin seed (Nigella sativa), which has higher binding affinity for HSA. Molecular docking simulations were performed to find the binding affinity of CMPF and DTQ with HSA. DTQ was found to have higher binding affinity possessing more interactions with the binding residues than the CMPF. We studied the binding pocket flexibility of CMPF and DTQ to analyze the binding abilities of both the compounds. We have also predicted the ADME properties for DTQ which shows higher lipophilicity, higher gastrointestinal (GI) absorption, and blood-brain barrier (BBB) permeability. We discovered that DTQ has potential to act as an inhibitor of CMPF and can be considered as a candidate for the formation of the therapeutic drug against CMPF.
Content may be subject to copyright.
Dithymoquinone as a novel inhibitor for 3-carboxy-4-
methyl-
5-propyl-2-furanpropanoic acid (CMPF) to prevent renal
Failure
(that we are currently working on)
Muniba Faiza1, Tariq Abdullah2, Prof. Yonghua Wang1*
1School of Food Science and Engineering, South China University of Technology, Guangzhou
510640, China; Email: muniba.faiza@gmail.com
2IQL Bioinformatics, Idea Quotient Labs, New Delhi, India; Email: tariq@ideaquotient.in
*Corresponding Author
Yonghua Wang, Ph.D.
Vice dean in the College of Light Industry and Food Sciences
School of Food Science and Engineering,
South China University of Technology,
Guangzhou, Guangdong Province, China 450001
Tel and Fax: 86-020-87113842
E-mail: yonghwang@scut.edu.cn
ABSTRACT
3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is a major endogenous ligand found
in the human serum albumin (HSA) of renal failure patients. It gets accumulated in the HSA and
its concentration in sera of patients may reflect the chronicity of renal failure [1-4]. It is
considered uremic toxin due to its damaging effect to the renal cells. The high concentrations of
CMPF inhibit the binding of other ligands to HSA . Removal of CMPF is difficult through
conventional hemodialysis due to i ts strong binding affinity. We hypothesized that the
competitive inhibition may be helpful in removal of CMPF binding to HSA. A compound with
higher HSA binding affinity than CMPF could be useful to prevent CMPF from binding so that
CMPF could be excreted by the body through the urine. We studied an active compound
dihydrothymoquinone/ dithymoquinone (DTQ) found in black cumin seed (Nigella sativa),
which has higher binding affinity for HSA. Molecular docking simulations were performed to
find the binding affinity of CMPF and DTQ with HSA. DTQ was found to have higher binding
affinity possessing more interactions with the binding residues than the CMPF. We studied the
binding pocket flexibility of CMPF and DTQ to analyze the binding abilities of both the
compounds. We have also predicted the ADME properties for DTQ which shows higher
lipophilicity, higher gastrointestinal (GI) absorption, and blood-brain barrier (BBB) permeability.
We discovered that DTQ has potential to act as an inhibitor of CMPF and can be considered as
a candidate for the formation of the therapeutic drug against CMPF.
KEYWORDS
CMPF, renal failure, black cumin seed (Nigella sativa), thymoquinone, dithymoquinone,
molecular docking, binding affinity.
INTRODUCTION
CMPF has been linked to the acute renal failure [1-3,5]. CMPF is a major endogenous toxin
retained in uremic serum and major drug-binding inhibitor [6]. The accumulation of CMPF
is caused by binding of CMPF to HSA, which cannot be removed through conventional
hemodialysis [7]. Currently, there is no known inhibitor for CMPF which can reduce its
accumulation.
Our Hypothesis
CMPF accumulation is due to its high binding affinity towards HSA among uremic toxins [8-
10]. We hypothesized that another compound with a higher binding affinity towards HSA than
CMPF should be able to bind with HSA. Thus, effectively blocking CMPF from binding. This
could have beneficial effects on human health apart from the effects on kidneys. The binding
of CMPF could be reduced leading to the decreased chances of acute renal failure. Assuming
this, we hypothetically considered a compound which has been earlier proved to be beneficial for
human health, such as cancer, tumor, and more [11-17]. This compound is dithymoquinone
(DTQ), one of the active compounds found in black cumin seed (Nigella sativa), which is
well known for its positive effects on human in various conditions such as tumor, cancer,
clearance of hepato-renal toxicity, diabetes, [8-18].and found to possessrelatively higher
binding affinity than CMPFWe predicted the inhibitory effect of DTQ against CMPF using in
silico docking performed by AutoDock tools [19]. In order to determine the capability of DTQ
as the potential drug candidate against CMPF, we predicted its ADME properties using
SwissADME [20]. The crucial role of CMPF in renal failure, binding with HSA, and DTQ
is discussed in detail in the following sections.
HSA- receptor for endogenous substances and drugs
HSA is an abundant plasma protein that belongs to a multigene family of proteins including α-
fetoprotein, vitamin-D binding protein, and human group specific component [21]. HSA binds to
a wide range of drugs and/ or endogenous ligands including bilirubin, thyroxine, non-esterified
fatty acids, and hemin [21], all of them being lipophilic, acidic compounds, in multiple sites [22-
27]. HSA protein consists of 585 amino acids with 17 disulphide bridges, one tryptophan residue
(Trp 214), and a single free-thiol (Cys 34) [28]. According to Sudlow et al., (1975) [29], there
are two binding sites in HSA: Site I and Site II. He & Carter (1992) [28] observed the binding
pockets of HSA lying in two subdomains: IIA and IIIA, which were the same sites but they
used different nomenclature to denote them. HSA is considered a silent receptor for drugs [30]
because it serves as a repository for a wide variety of compounds as the negative charge on HSA
facilitates the electrostatic binding of various ligands and acts as a depot and carrier for many
drug compounds [31-34]. Due to the presence of limited number of high- affinity binding
sites in HSA, detailed molecular information about these sites could be helpful in studying the
effects of other drugs or ligands and the structural information of both low- and high- affinity
binding sites is useful in designing new drugs with the aim either avoiding binding to HSA or to
make use of its functions [35].
CMPF is a metabolite of F-acids [36-40] which was first detected in human urine [37] and then
later in human blood [38]. CMPF is considered as one of the major drug- binding inhibitor [1,6,41-
43]. The drug-binding effect observed in vivo that the CMPF levels rise in kidney patients are due
to the specific steric blocking of drug site 1 by this compound [43,44]. Sakai et al., (1995) [44]
studied the interactions of CMPF in comparison of other three uremic toxins: indoxyl sulphate,
indole acetic acid, and hippuric acid using fluorescent probe displacement, ultrafiltration, and
equilibrium dialysis. The results showed that CMPF had the highest binding affinity (10-7 M-1)
among the three uremic toxins. As compared with the other uremic toxins, CMPF consists of
least rate of elimination and the most potent inhibitor [10,44-47]. Several studies have
demonstrated that uremic toxins are involved in the production of reactive oxygen species
(ROS) [48-50]. In a study conducted by Miyamoto et al., (2012) [50], it was shown that
CMPF induces the renal cell damage by enhancing the production of ROS in the presence of
Angiotensin-II (A-II), which is an inducer of oxygen free radicals. Also, in the presence of iron,
CMPF and A-II induce the Fenton's reaction leading to an increase in ROS production. The
subsequent interaction of CMPF with dissolved oxygen leads to the overproduction of oxygen
free radicals.
All the experiments mentioned above are sufficient enough to prove the damaging role of
CMPF in renal failure because they have used reliable techniques (GC-MS, HPLC, etc.) to study
the levels of CMPF in uremic/ dialyzed patients. On the basis of these findings, we can conclude
that CMPF is responsible for renal failure by getting accumulated in the renal cells and due to
its prooxidant nature, it increases the ROS production in the endothelial cells, which ultimately
leads to the renal cellular damage. Another role of CMPF in renal damage which may not be
denied is its ability to bind very strongly to HSA making itself a strong potent inhibitor resulting
in accumulation and ultimately to renal failure. It may be of great importance to remove
accumulated CMPF from HSA to prevent renal failure due to its inhibiting properties. Other
compounds cannot easily replace CMPF which has a higher binding affinity. Addressing this
major problem, we have shown that, DTQ - a compound which is already well- known for its
beneficial effects on human health, and an active component of black cumin seed (Nigella
sativa) has higher binding affinity towards HSA than the CMPF and higher lipophilicity due to
which it may be proven as a potential drug candidate in curing renal failure caused by CMPF.
Black Cumin Seed (Nigella sativa)
CMPF being the major drug-binding inhibitor, its binding with HSA could be restricted using any
other compound with higher binding affinity and high therapeutic efficacy. Black cumin seed
(Nigella sativa) has been known for its therapeutic efficiencies since many centuries. It has
been referred in Islamic tradition as having healing powers [51]. It is a spice grown in
Mediterranean region and in Western Asian countries such as India, Afghanistan, and Pakistan.
The historical references to the seeds are also found in some of the oldest religious medical
texts such as it is referred by Hippocrates and Dioscorides as ‘Melanthion’, the Bible describes it
as the curative black cumin (Isaiah 28:25, 27 NKJV), and according to hadith, Islamic messenger
Prophet Muhammad (PBUH) said “In the black seed is healing for every disease except death”
(Sahih Bukhari).
Black cumin seeds have also been used in traditional medicines for many past years for the
treatment of a wide range of diseases including a headache, bronchial asthma, infections,
dysentery, back pain, hypertension, and gastrointestinal problems [52]. The pharmacological
investigations of black cumin seed extracts have revealed its potential broad spectrum activities
as antihistaminic [53], antimicrobial [54], anti-diabetic [55], anti-hypertensive [56],
immunopotentiation [57], and anti-inflammatory [58]. It has also been proved to be consisting
of anti-tumor [12] and anticancer activities [59-61].
DTQ- a solution to CMPF accumulation problem
The bioactive constituents of the volatile black seed oil were first identified by Al-Dakhakhany
(1963) [62] showing thymoquinone (TQ) as the most active constituent (about 54%) among the
others. Later on, other active compounds: DTQ, thymol (THY), and thymohydroquinone (THQ)
were identified by Ghosheh et al., (1999) [11] using HPLC. TQ (2-isopropyl-5-methyl-
1,4-benzoquinone) has been shown to exhibit anti-inflammatory, anti-oxidant, anti-neoplastic
activities both in-vivo and in-vitro [63]. DTQ, THY, and THQ are more likely the metabolites
of TQ as under physiological conditions, TQ gets slowly reduced to DTQ and THY [64].
TQ has been shown to possess antioxidant properties through different mechanisms such as it
inhibits the formation of 5-hydroxyeicosa-tetraenaoic as well as 5-lipoxygenase products [65]
which are required for the viability of colon cancer cells. Most importantly, in the context of this
study, TQ has been shown to act as a scavenger to various ROS [66-68]. The molecular surfaces
of TQ and DTQ possess significant amount of positively charged electron-deficit regions so that
they may be subjected to nucleophilic attacks by glutathione and nucleotide bases in DNA,
thereby, causing cellular toxicity due to the depletion of glutathione and damage of DNA due to
the oxidation of nucleotide bases.
Badary et al., (1997) [69] studied the effects of TQ on cisplatin-induced nephrotoxicity and
concluded that TQ ameliorates the nephrotoxicity in rodents and induce the anti-tumor activity
of cisplatin. Due to the antioxidative and anti-inflammatory properties of TQ, it acts against
renal injuries [15]. Fouda et al., (2008) [70] studied the effects of TQ on renal oxidative damage
and proliferative response induced by mercuric chloride in rats and based on their results it was
concluded that it may be a clinically valuable agent in the prevention of acute renal failure
caused by inorganic mercury intoxication. Similarly, Hamed et al., (2013) [17] studied the
effects of black cumin seed oil on hepato-renal injury induced by bromobenzene exposure.
They concluded that the treatment with black seed oil significantly enhanced the hepato-renal
protection mechanism, reduced disease complications, and delayed its progression [17].
All these investigations done earlier supports that renal failure/damage can be
prevented/treated with black cumin seed due to the presence of anti-oxidative component TQ
and/ DTQ. TQ and DTQ both are similar in a way that they both have oxygen atoms on 1,4-
positions of the benzene ring (Fig. 1), which contribute to their anti-oxidative properties. In this
study, we performed docking experiments on HSA with DTQ (having same properties as TQ)
and HSA with CMPF and found that DTQ was able to bind more effectively than CMPF.
Therapeutics available for uremic ailments
Numerous uremic toxins such as indoles and phenols were detected for the first time in uremic
plasma between the 1940s and 1990s [71-73]. It has been proved that a majority of uremic
toxins originate endogenously through mammalian metabolism and therefore, it is being
increasingly recognized that intestinal microbial metabolism has a large effect on mammalian
blood metabolites resulting in the formation of various uremic toxins such as indoxyl sulphate,
p-cresol sulphate, etc. [74-76]. CMPF, which is also a uremic toxin, is said to a metabolite of F-
acids [36-40] and there are still no evidence to locate the place of its metabolization in humans.
There are two main existing therapeutic approaches to treat ailment caused by uremic toxins:
1) interventions that modulate bacterial growth such as probiotics, prebiotics, and dietary
modifications. 2) adsorbents that bind uremic toxins to reduce their absorption by the host.
Both of these approaches are based on the fact that these uremic toxins are metabolized by the
gut microbiota, but in the case of CMPF, it is still rendered questionable. However, the
adsorbent approach is sometimes not helpful in retarding the progression of chronic kidney
disease, for example, Sevelamer hydrochloride (Renagel; Genzyme, Cambridge, MA, USA) has
been shown to bind some of the uremic toxins such as indoxyl sulphate (10-15%) and p-cresol
(40-50%, depending on pH) [77], but it did not result in decreased serum concentrations of
these uremic toxins in a mouse model of chronic kidney disease. However, the treatment of
sevelamer in humans for studying the alterations in serum concentrations of microbial
metabolites remains to be investigated.
METHODS
Retrieval of the structures
The 3D structures of DTQ and CMPF were downloaded from PubChem (PubChem CID: 398941
and PubChem CID: 123979, respectively). The protein crystal structure of HSA was downloaded
from Protein Data Bank (PDB ID: 2BXA) [78].
Molecular docking simulations
As revealed by Ghuman et al., (2005) [78], CMPF binds to the Y-150, R-257, H-242, R-222, and
K-199 in the site I of HSA. Molecular docking simulations were done by AutoDock Vina [19].
CMPF and DTQ were docked with HSA by having default x, y, and z coordinates, i.e., 40 for
each, and the center coordinates were set accordingly. The docking results were analyzed using
PyMol [79].
Binding Analysis
Some of the factors which were influenced by binding of CMPF and DTQ with HSA were
analyzed by BINANA software [80]. BINANA (BINding ANAlyzer) is a python-
implemented algorithm to analyze ligand binding. This software analyzes the key binding
characteristics such as pi-pi interactions, hydrogen bonds, salt bridges, etc. In this study, we
used BINANA to identify the active-site flexibility of CMPF and DTQ with HSA. The results
are shown in Table 1.
ADME properties analysis
The ADME properties of DTQ were predicted by SwissADME software [20]. The
ADME properties predicted by the SwissADME include physicochemical properties,
lipophilicity, water solubility, pharmacokinetics, drug-likeness, and medicinal chemistry.
These properties are shown in Table 2.
RESULTS
Docking simulation results
Docking results showed that DTQ bound more effectively than CMPF showing the higher
binding affinity (-8.1 kcal/mol) than the later (-7.0 kcal/mol). DTQ was able to occupy the
binding pocket more efficiently than the CMPF (Fig. 2A and 2B). Docking simulations of
CMPF with HSA showed the interaction with four residues of HSA: Y150, K199, R222, and
R257 having the bond lengths equal to 2.9 A, 3.0 A, 3.0 A, and 3.2 A respectively (Fig. 3A).
Similarly, DTQ bound with Y150, K199, R222, and R257 residues of HSA having the bond
lengths equal to 3.0 A, 2.7 A, 3.0 A, and 3.2 A respectively (Fig. 3B). The bond lengths
formed by DTQ are comparatively smaller than that of CMPF, this is the another parameter to
support that DTQ is capable of binding more efficiently than CMPF and since the former bound
at the same position as the later one, we can conclude that DTQ may be a potent inhibitor of CMPF.
Fig. 2 Binding pocket of HSA A) CMPF B) DTQ. DTQ bind in the same pocket as CMPF in
HSA and covers the binding site more efficiently than the CMPF.
Fig. 3 Representing the interaction and bond lengths of A) CMPF and B) DTQ with HSA.
DTQ showed shorter bond lengths with the interacting residues than that of CMPF.
Binding Analysis results
According to Koshland, the active-site residues usually adjust to allow the binding of a specific
substrate [81]. The induced-fit model assumes that the active site is flexible and changes shape
to allow the complete binding of a substrate [82], which is a case here for CMPF and DTQ
binding with HSA. BINANA categorizes each atom into six possible characterizations: alpha
sidechain, alphabackbone, beta sidechain, beta backbone, othersidechain, and other
backbone. The number of close contact receptor atoms falling under each of these six
categories is tallied as a metric of bindingsite flexibility. According to the predicted results of
BINANA, DTQ showed more flexibility than CMPF towards the backbone and the side-
chain (Table 1). These results suggest that the binding residues of HSA have to undergo
more conformational changes for DTQ which may be due to the more complex structure than that
of CMPF, and it may also contribute to the higher binding affinity of the former than the later.
Table 1 Binding pocket flexibility properties of CMPF and DTQ.
Ligand
Side-chain/
Backbone
Secondary structure
Count
CMPF
Side-chain
Alpha
153
Backbone
Alpha
111
DTQ
Side-chain
Alpha
208
Backbone
Alpha
153
Side-chain
Other
4
ADME properties
The ADME properties of DTQ were predicted in order to determine its lipophilicity. Lipophilicity
is one of the important parameters which is considered for drug candidates metabolism,
greater the lipophilicity, more is the absorption. The ADME results are shown in Table 2.
Table 2 ADME properties of CMPF and DTQ predicted by SwissADME.
ADME properties
DTQ
Molecular weight
328.40 g/mol
Lipophilicity (WLogP)
2.71
Consensus Log Po/w
2.62
Water Solubility (ESOL)
-3.05
GI absorption
High
BBB permeant
Yes
Log Kp (skin permeation)
-6.83 cm/s
Lipinski rule
Yes
Leadlikeness
Yes
Synthetic accessibility
4.65
Lipophilicity is the ability of the compound to dissolve in lipophilic solutions to permeate
through the various biological membranes. It is measured the distribution of the compound
between the non-aqueous (octanol) and the aqueous (water) phase, and the result is expressed
as the logarithm of the concentration ratios termed as logP. A desired logP value is less than 5.0
[83]. In the case of DTQ, the estimated logP value is 2.62, which shows its higher lipophilicity.
The BBB permeability is not considered good for the compounds as it may cause other harmful
effects to the brain, but in the case of black cumin seed, it has been found that it causes beneficial
neuropsychiatric effects and helps in to improve memory, and mood [84-86].
BOILED-Egg results predicted by SwissADME
Brain Or IntestinaL EstimateD permeation (BOILED-Egg) method predicts an accurate model
to analyze the gastrointestinal (GI) absorption and blood-brain barrier (BBB) of the candidate
drugs [87]. It works by calculating the lipophilicity and polarity of the molecules. The BOILED-
Egg representation of DTQ is shown in Fig. 4. The white region represents the physicochemical
space of the molecule possessing the highest probability of absorption by the GI tract, whereas
the yellow region represents the physicochemical space of the molecule having the highest
probability to permeate the brain. According to the BOILED-Egg representation generated by
the SwissADME, DTQ has high GI absorption and the BBB permeability (Fig. 4).
CONCLUSION AND FUTURE DEVELOPMENTS
In this study we attempted to provide an insight into the role of CMPF in renal failure as implicated
by many studies since quiet a time. CMPF has been found to be involved in causing type 2 diabetes
by disrupting the beta-cell function [88-91], but it stands contradictory as some of the research
does not correlate CMPF with diabetes [92,93] and also due to the lack of evidences CMPF has
not been positively correlated with diabetes [94]. Therefore, we have addressed only the problem
of CMPF binding with HSA leading to its accumulation and causing renal failure. According to
the studies mentioned above, the capability of CMPF to bind strongly with HSA has posed a
difficult task to remove the accumulated CMPF from the renal tubular cells. In this paper, we have
proposed a suitable solution for the situation through in silico studies. We conclude that DTQ is
capable to bind more strongly to HSA than the CMPF and shows inhibitory effects, which requires
further in vitro studies to elucidate its actual mechanism of inhibition. The past publications
provide sufficient evidences regarding the health benefits of active components of black cumin
seed (Nigella sativa), therefore, we can conclude that DTQ possess many health benefits for
humans due to its capability to bind with HSA more efficiently than CMPF, making it the best
possible solution for inhibition of CMPF binding to HSA. Also, as CMPF is a strong lipophilic
uremic solute (Depner, 1981), therefore, we comparatively analyzed the ADME properties of DTQ
and CMPF in silico. According to the predicted ADME properties, DTQ could be considered as
the potential drug candidate against the action of CMPF and can be further utilised to make
therapeutic drugs to treat renal failure caused by the accumulation of CMPF in renal cells.
Conflict of Interest
Authors declare that there is no conflict of interest whatsoever.
Declaration
MF and TA conceived the idea and performed the experiments. MF, TA and YW wrote the
manuscript.
REFERENCES
1. Mabuchi, H., & Nakahashi, H. (1988a). Inhibition of hepatic glutathione S-transferases by a major
endogenous ligand substance present in uremic serum. Nephron, 49(4), 281-283.
2. Mabuchi, H., & Nakahashi, H. (1988b). A major endogenous ligand substance involved in renal
failure. Nephron, 49(4), 277-280.
3. Mabuchi, H., & Nakahashi, H. (1990). Endogenous ligands that bind to serum albumin and renal
failure. Nephron, 55(1), 81-82.
4. Sato, M., Koyama, M., Miyazaki, T., & Niwa, T. (1996). Reduced renal clearance of
furancarboxylic acid, a major albumin-bound organic acid, in undialyzed uremic patients.
Nephron, 74(2), 419-421.
5. Niwa, T. (1996, May). Organic acids and the uremic syndrome: protein metabolite hypothesis in
the progression of chronic renal failure. In Seminars in nephrology (Vol. 16, No. 3, pp. 167-182).
6. Mabuchi, H., & Nakahashi, H. (1988c). A major inhibitor of phenytoin binding to serum protein
in uremia. Nephron, 48(4), 310-314.
7. Itoh, Y., Ezawa, A., Kikuchi, K., Tsuruta, Y., & Niwa, T. (2012). Protein-bound uremic toxins in
hemodialysis patients measured by liquid chromatography/tandem mass spectrometry and their
effects on endothelial ROS production. Analytical and bioanalytical chemistry, 403(7), 1841-
1850.
8. Mabuchi, H., & Nakahashi, H. (1987). Underestimation of serum albumin by the bromcresol
purple method and a major endogenous ligand in uremia. Clinica chimica acta, 167(1), 89-96.
9. Niwa, T. (1996, May). Organic acids and the uremic syndrome: protein metabolite hypothesis in
the progression of chronic renal failure. In Seminars in nephrology (Vol. 16, No. 3, pp. 167-182).
10. Sarnatskaya, V. V., Lindup, W. E., Niwa, T., Ivanov, A. I., Yushko, L. A., Tjia, J., ... & Nikolaev,
V. G. (2002). Effect of protein-bound uraemic toxins on the thermodynamic characteristics of
human albumin. Biochemical pharmacology, 63(7), 1287-1296.
11. Ghosheh, O. A., Houdi, A. A., & Crooks, P. A. (1999). High performance liquid chromatographic
analysis of the pharmacologically active quinones and related compounds in the oil of the black
seed (Nigella sativa L.). Journal of pharmaceutical and biomedical analysis, 19(5), 757-762.
12. Ait Mbarek, L., Ait Mouse, H., Elabbadi, N., Bensalah, M., Gamouh, A., Aboufatima, R., ... &
Zyad, A. (2007). Anti-tumor properties of blackseed (Nigella sativa L.) extracts. Brazilian
Journal of Medical and Biological Research, 40(6), 839-847.
13. Padhye, S., Banerjee, S., Ahmad, A., Mohammad, R., & Sarkar, F. H. (2008). From here to
eternity-the secret of Pharaohs: Therapeutic potential of black cumin seeds and beyond. Cancer
therapy, 6(b), 495.
14. Sultan, M. T., Butt, M. S., Anjum, F. M., Jamil, A., Akhtar, S., & Nasir, M. (2009). Nutritional
profile of indigenous cultivar of black cumin seeds and antioxidant potential of its fixed and
essential oil. Pak J Bot, 41(3), 1321-1330.
15. Ragheb, A., Attia, A., Eldin, W. S., Elbarbry, F., Gazarin, S., & Shoker, A. (2009). The protective
effect of thymoquinone, an anti-oxidant and anti-inflammatory agent, against renal injury: a
review. Saudi Journal of Kidney Diseases and Transplantation, 20(5), 741.
16. Huq, F., & Mazumder, E. H. (2010). Molecular modelling analysis of the metabolism of
thymoquinone.
17. Hamed, M. A., & Ali, S. A. (2013). Effects of black seed oil on resolution of hepato-renal toxicity
induced by bromobenzene in rats. Eur Rev Med Pharmacol Sci, 17(5), 569-81.
18. Mathur, M. L., Gaur, J., Sharma, R., & Haldiya, K. R. (2011). Antidiabetic properties of a spice
plant Nigella sativa. Journal of Endocrinology and Metabolism, 1(1), 1-8.
19. Trott, O., & Olson, A. J. (2010). AutoDock Vina: improving the speed and accuracy of docking
with a new scoring function, efficient optimization, and multithreading. Journal of computational
chemistry, 31(2), 455-461.
20. Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules. Scientific Reports, 7, 42717.
21. Peters, T. (1995). All About Albumin: Biochemistry, Genetics and Medical Applications,
Academic Press, San Diego.
22. Curry, S., Mandelkow, H., Brick, P. & Franks, N. (1998). Crystal structure of human serum
albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nature
Struct. Biol. 5, 827835.
23. Bhattacharya, A. A., Gru¨ne, T. & Curry, S. (2000). Crystallographic analysis reveals common
modes of binding of medium and long-chain fatty acids to human serum albumin. J. Mol. Biol.
303, 721732
24. Petitpas, I., Gru ¨ne, T., Bhattacharya, A. A. & Curry, S. (2001). Crystal structures of human
serum albumin complexed with monounsaturated and polyunsaturated fatty acids. J. Mol. Biol.
314, 955960.
25. Wardell, M., Wang, Z., Ho, J. X., Robert, J., Ruker, F., Ruble, J. & Carter, D. C. (2002). The
atomic structure of human methemalbumin at 1.9 A ˚ . Biochem. Biophys. Res. Commun. 291,
813819.
26. Petitpas, I., Petersen, C. E., Ha, C. E., Bhattacharya, A. A., Zunszain, P. A., Ghuman, J. et al.
(2003). Structural basis of albuminthyroxine interactions and familial dysalbuminemic
hyperthyroxinemia. Proc. Natl Acad. Sci. USA, 100, 64406445.
27. Zunszain, P. A., Ghuman, J., Komatsu, T., Tsuchida, E. & Curry, S. (2003). Crystal structural
analysis of human serum albumin complexed with hemin and fatty acid. BMC Struct. Biol. 3, 6
28. He, X. M., & Carter, D. C. (1992). Atomic structure and chemistry of human serum albumin.
29. Sudlow, G.D.J.B., Birkett, D.J. and Wade, D.N., (1975). The characterization of two specific drug
binding sites on human serum albumin. Molecular Pharmacology, 11(6), pp.824-832.
30. Müller, W. E., & Wollert, U. (1979). Human serum albumin as a ‘silent receptor’ for drugs and
endogenous substances. Pharmacology, 19(2), 59-67.
31. Lejon, S., Frick, I. M., Björck, L., Wikström, M., & Svensson, S. (2004). Crystal structure and
biological implications of a bacterial albumin binding module in complex with human serum
albumin. Journal of biological chemistry, 279(41), 42924-42928.
32. Fasano, M., Curry, S., Terreno, E., Galliano, M., Fanali, G., Narciso, P., ... & Ascenzi, P. (2005).
The extraordinary ligand binding properties of human serum albumin. IUBMB life, 57(12), 787-
796.
33. Ascoli, G. A., Domenici, E., & Bertucci, C. (2006). Drug binding to human serum albumin:
Abridged review of results obtained with highperformance liquid chromatography and circular
dichroism. Chirality, 18(9), 667-679.
34. Yang, F., Zhang, Y., & Liang, H. (2014). Interactive association of drugs binding to human
serum albumin. International journal of molecular sciences, 15(3), 3580-3595.
35. Hein, K. L., Kragh-Hansen, U., Morth, J. P., Jeppesen, M. D., Otzen, D., Møller, J. V., & Nissen,
P. (2010). Crystallographic analysis reveals a unique lidocaine binding site on human serum
albumin. Journal of structural biology, 171(3), 353-360.
36. Schödel, R., Dietel, P., and Spiteller, G. (1986) F-Säuren als Vorstufen der Urofuransäuren,
Liebigs Ann. Chem., 127131.
37. Spiteller M, Spiteller G. (1979). Separation and characterization of acidic urine constituents
(author's transl). Journal of Chromatography [1979, 164(3):253-317]. PMID:544607
38. Spiteller, M., Spiteller, G., & Hoyer, G. A. (1980). Urofuransäureneine bisher unbekannte
Klasse von Stoffwechselprodukten. Chemische Berichte, 113(2), 699-709.
39. Pfordt, J., Thoma, H. and Spiteller, G., (1981). Identifizierung, Strukturableitung und Synthese
bisher unbekannter Urofuransäuren im menschlichen Blut. Liebigs Annalen der
Chemie, 1981(12), pp.2298-2308.
40. Wahl, H. G., Tetschner, B., & Liebich, H. M. (1992). The effect of dietary fish oil
supplementation on the concentration of 3carboxy4methyl5propyl2furanpropionic acid in
human blood and urine. Journal of High Resolution Chromatography, 15(12), 815-818.
41. Costigan, M.G., and Lindup, W.E. (1996) Plasma Clearance in the Rat of Furan Dicarboxylic
Acid Which Accumulates in Uremia, Kidney Int. 49, 634638.
42. Deguchi, T., Kusuhara, H., Takadate, A., Endou, H., Otagiri, M. and Sugiyama, Y., (2004).
Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney
international, 65(1), pp.162-174.
43. Henderson, S.J., and Lindup, E. (1992) Renal Organic Acid Transport: Uptake by Rat Kidney
Slices of a Furan Dicarboxylic Acid Which Inhibits Plasma Protein Binding of Acidic Ligands in
Uremia, J. Pharmacol. Exp. Ther. 263, 5460.
44. Sakai, Takadate A., Otagiri M. (1995). Characterization of binding site of uremic toxins on human
serum albumin [J]. Biological and Pharmaceutical Bulletin. 18(12): 1755-1761.
45. Tsutsumi Y, Deguchi T, Takano M, et al (2002). Renal disposition of a furan dicarboxylic acid
and other uremic toxins in the rat[J]. Journal of Pharmacology and Experimental Therapeutics.
303(2): 880-887.
46. Lim, C. F., Bernard, B. F., De Jong, M., Docter, R., Krenning, E. P., & Hennemann, G. (1993).
A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport
in uremia. The Journal of Clinical Endocrinology & Metabolism, 76(2), 318-324.
47. Franke, R. M., & Sparreboom, A. (2008). Inhibition of imatinib transport by uremic toxins during
renal failure. Journal of Clinical Oncology, 26(25), 4226-4227.
48. Motojima, M., Hosokawa, A., Yamato, H., Muraki, T., & Yoshioka, T. (2003). Uremic toxins of
organic anions up-regulate PAI-1 expression by induction of NF-κB and free radical in proximal
tubular cells. Kidney international, 63(5), 1671-1680.
49. Shimoishi, K., Anraku, M., Kitamura, K., Tasaki, Y., Taguchi, K., Hashimoto, M., ... & Otagiri,
M. (2007). An oral adsorbent, AST-120 protects against the progression of oxidative stress by
reducing the accumulation of indoxyl sulfate in the systemic circulation in renal failure.
Pharmaceutical research, 24(7), 1283-1289.
50. Miyamoto Y, Iwao Y, Mera K, et al (2012). A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-
furanpropionate induces cell damage to proximal tubular cells via the generation of a radical
intermediate [J]. Biochemical pharmacology. 84(9): 1207-1214.
51. Goreja, W. G. (2003). Black Seed: Natural Medical Remedy. Amazing Herbs.
52. Al-Rowais, N. A. (2002). Herbal medicine in the treatment of diabetes mellitus. Saudi medical
journal, 23(11), 1327-1331.
53. Mahfouz, M., ABDELMAG. R, & ELDAKHAK. M. (1965). EFFECT OF NIGELLONE-
THERAPY ON HISTAMINOPEXIC POWER OF BLOOD SERA OF ASTHMATIC
PATIENTS. Arzneimittel-forschung, 15(10), 1230.
54. El-Fatatry, H. M. (1975). Isolation and structure assignment of an antimicrobial principle from
the volatile oil of Nigella sativa L. seeds. Die Pharmazie, 30(2), 109-111.
55. Al-Hader, A., Aqel, M., & Hasan, Z. (1993). Hypoglycemic effects of the volatile oil of Nigella
sativa seeds. International journal of pharmacognosy, 31(2), 96-100.
56. El Tahir, K. E., Ashour, M. M., & Al-Harbi, M. M. (1993). The cardiovascular actions of the
volatile oil of the black seed (Nigella sativa) in rats: elucidation of the mechanism of action.
General Pharmacology: The Vascular System, 24(5), 1123-1131.
57. Medinica, R., Mukerjee, S., Huschart, T., & Corbitt, W. (1994, April). Immunomodulatory and
anticancer activity of Nigella sativa plant extract in humans. In Proceedings of the American
Association for Cancer Research Annual Meeting (p. A2865).
58. Houghton, P. J., Zarka, R., de las Heras, B., & Hoult, J. R. S. (1995). Fixed oil of Nigella sativa
and derived thymoquinone inhibit eicosanoid generation in leukocytes and membrane lipid
peroxidation. Planta medica, 61(01), 33-36.
59. Khan, A., Chen, H. C., Tania, M., & Zhang, D. Z. (2011). Anticancer activities of Nigella sativa
(black cumin). African Journal of Traditional, Complementary and Alternative Medicines, 8(5S).
60. Harzallah, H. J., Kouidhi, B., Flamini, G., Bakhrouf, A., & Mahjoub, T. (2011). Chemical
composition, antimicrobial potential against cariogenic bacteria and cytotoxic activity of Tunisian
Nigella sativa essential oil and thymoquinone. Food Chemistry, 129(4), 1469-1474.
61. Randhawa, M. A., & Alghamdi, M. S. (2011). Anticancer activity of Nigella sativa (black seed)
a review. The American journal of Chinese medicine, 39(06), 1075-1091.
62. Al-Dakhakhany, M. (1963). Studies on the chemical constituition of Egyptian Nigella sativa L
seeds. Planta Med, 1, 465-470.
63. Gali-Muhtasib, H., Roessner, A., & Schneider-Stock, R. (2006). Thymoquinone: a promising
anti-cancer drug from natural sources. The international journal of biochemistry & cell biology,
38(8), 1249-1253.
64. Khalife, K. H., & Lupidi, G. (2007). Nonenzymatic reduction of thymoquinone in physiological
conditions. Free radical research, 41(2), 153-161.
65. El-Dakhakhny, M., Madi, N. J., Lembert, N., & Ammon, H. P. T. (2002). Nigella sativa oil,
nigellone and derived thymoquinone inhibit synthesis of 5-lipoxygenase products in
polymorphonuclear leukocytes from rats. Journal of ethnopharmacology, 81(2), 161-164.
66. Kruk, I., Michalska, T., Lichszteld, K., Kładna, A., & Aboul-Enein, H. Y. (2000). The effect of
thymol and its derivatives on reactions generating reactive oxygen species. Chemosphere, 41(7),
1059-1064.
67. Mansour, M. A., Nagi, M. N., ElKhatib, A. S., & AlBekairi, A. M. (2002). Effects of
thymoquinone on antioxidant enzyme activities, lipid peroxidation and DTdiaphorase in
different tissues of mice: a possible mechanism of action. Cell biochemistry and function, 20(2),
143-151.
68. Badary, O. A., Taha, R. A., Gamal El-Din, A. M., & Abdel-Wahab, M. H. (2003). Thymoquinone
is a potent superoxide anion scavenger. Drug and chemical toxicology, 26(2), 87-98.
69. Badary, O. A., Nagi, M. N., Al-Shabanah, O. A., Al-Sawaf, H. A., Al-Sohaibani, M. O., & Al-
Bekairi, A. M. (1997). Thymoquinone ameliorates the nephrotoxicity induced by cisplatin in
rodents and potentiates its antitumor activity. Canadian Journal of Physiology and
Pharmacology, 75(12), 1356-1361.
70. Fouda, A. M. M., Daba, M. H. Y., Dahab, G. M., & Sharaf elDin, O. A. (2008). Thymoquinone
ameliorates renal oxidative damage and proliferative response induced by mercuric chloride in
rats. Basic & clinical pharmacology & toxicology, 103(2), 109-118.
71. LUDWIG, G. D., SENESKY, D., Bluemlef, L. W., & ELKINTON, J. R. (1968). Indoles in
uremia: identification by countercurrent distribution and paper chromatography. The American
journal of clinical nutrition, 21(5), 436-450.
72. Toshimitsu, N., Kenji, M., Toyokazu, O., Akira, S., & Kaizo, K. (1981). A gas chromatographic-
mass spectrometric analysis for phenols in uremic serum. Clinica Chimica Acta, 110(1), 51-57.
73. Van Haard, P. M., & Pavel, S. (1988). Chromatography of urinary indole derivatives. Journal of
Chromatography B: Biomedical Sciences and Applications, 429, 59-94.
74. Wikoff, W. R., Anfora, A. T., Liu, J., Schultz, P. G., Lesley, S. A., Peters, E. C., & Siuzdak, G.
(2009). Metabolomics analysis reveals large effects of gut microflora on mammalian blood
metabolites. Proceedings of the national academy of sciences, 106(10), 3698-3703.
75. Niwa, T. (2009). Recent progress in the analysis of uremic toxins by mass spectrometry. Journal
of Chromatography B, 877(25), 2600-2606.
76. Rhee, E. P., Souza, A., Farrell, L., Pollak, M. R., Lewis, G. D., Steele, D. J., ... & Gerszten, R. E.
(2010). Metabolite profiling identifies markers of uremia. Journal of the American Society of
Nephrology, 21(6), 1041-2051.
77. De Smet, R., Thermote, F., Lameire, N., & Vanholder, R. (2004). Sevelamer Hydrochloride
(renagel®) Adsorbs The Uremic Compound Indoxyl Sulfate. The International Journal of
Artificial Organs, 27(7), 569.
78. Ghuman, J., Zunszain, P. A., Petitpas, I., Bhattacharya, A. A., Otagiri, M., & Curry, S. (2005).
Structural basis of the drug-binding specificity of human serum albumin. Journal of molecular
biology, 353(1), 38-52
79. DeLano, W. L. (2002). The PyMOL molecular graphics system.
80. Durrant, J. D., & McCammon, J. A. (2011). BINANA: a novel algorithm for ligand-binding
characterization. Journal of Molecular Graphics and Modelling, 29(6), 888-893.
81. Koshland, D. E. (1959). Enzyme flexibility and enzyme action. Journal of cellular and
comparative physiology, 54(S1), 245-258.
82. Sullivan, S. M., & Holyoak, T. (2008). Enzymes with lid-gated active sites must operate by an
induced fit mechanism instead of conformational selection. Proceedings of the National Academy
of Sciences, 105(37), 13829-13834.
83. Novamass- http://www.sbw.fi/lead-optimization/experimental-logp-logd-logs-pka-analysis/
84. Akhondian, J., Parsa, A., & Rakhshande, H. (2007). The effect of Nigella sativa L.(black cumin
seed) on intractable pediatric seizures. Medical Science Monitor, 13(12), CR555-CR559.
85. Alenazi, S. A. (2016). Neuropsychiatric Effects of Nigella sativa (Black Seed) A
Review. Alternative & Integrative Medicine.
86. Beheshti, F., Khazaei, M., & Hosseini, M. (2016). Neuropharmacological effects of Nigella
sativa. Avicenna journal of phytomedicine, 6(1), 104.
87. Daina, A., & Zoete, V. (2016). A BOILED‐Egg To Predict Gastrointestinal Absorption and Brain
Penetration of Small Molecules. ChemMedChem, 11(11), 1117-1121.
88. Prentice K J, Luu L, Allister E M, et al (2014). The furan fatty acid metabolite CMPF is elevated
in diabetes and induces cell dysfunction[J]. Cell metabolism. 19(4): 653-666.
89. Liu Y, Prentice K J, Eversley J A, et al (2016). Rapid elevation in CMPF may act as a tipping
point in diabetes development [J]. Cell reports. 14(12): 2889-2900.
90. Retnakaran R, Ye C, Kramer C K, et al. (2016). Evaluation of circulating determinants of beta-
cell function in women with and without gestational diabetes [J]. The Journal of Clinical
Endocrinology & Metabolism, 2016: jc. 2016-1402.
91. Lu Y, Wang Y, Ong C N, et al. (2016). Metabolic signatures and risk of type 2 diabetes in a
Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS[J].
Diabetologia. 59(11): 2349-2359.
92. Lankinen M A, Hanhineva K, Kolehmainen M, et al. (2015). CMPF does not associate with
impaired glucose metabolism in individuals with features of metabolic syndrome[J]. PloS one
10(4): e0124379.
93. Zheng J S, Lin M, Imamura F, et al (2016). Serum metabolomics profiles in response to n-3 fatty
acids in Chinese patients with type 2 diabetes: a double-blind randomised controlled trial[J].
Scientific Reports. 6.
94. Wallin, A., Di Giuseppe, D., Orsini, N., Patel, P.S., Forouhi, N.G. and Wolk, A., (2012). Fish
consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes. Diabetes care, 35(4),
pp.918-929.
Figure legends
Fig.1 2D structure of a) TQ b) DTQ
Fig. 2 Binding pocket of HSA A) CMPF B) DTQ. DTQ bind in the same pocket as CMPF in
HSA and covers the binding site more efficiently than the CMPF.
Fig. 3 Representing the interaction and bond lengths of A) CMPF and B) DTQ with HSA.
DTQ showed shorter bond lengths with the interacting residues than that of CMPF.
Fig. 4 BOILED-Egg representation of DTQ. Yellow region represents the BBB and the white
region represents the GI absorption, and red circle represents the molecule (i.e., DTQ).
Fig.1 2D structure of a) TQ b) DTQ
Fig. 2 Binding pocket of HSA A) CMPF B) DTQ. DTQ bind in the same pocket as
CMPF in HSA and covers the binding site more efficiently than the CMPF.
Fig. 3 Representing the interaction and bond lengths of A) CMPF and B) DTQ with HSA.
DTQ showed shorter bond lengths with the interacting residues than that of CMPF.
Fig. 4 BOILED-Egg representation of DTQ. Yellow region represents the BBB and the
white region represents the GI absorption, and red circle represents the molecule (i.e., DTQ).
... In addition, thymoquinone is present in its dimeric form as well, which is commonly known as dithymoquinone or nigellone. Dithymoquinone has shown progressive effects on humans during renal-hepatic toxicity, diabetes, and cancer [34][35][36]. ...
Article
Full-text available
Background: The outbreak of the coronavirus (SARS-CoV-2) has drastically affected the human population and caused enormous economic deprivation. It belongs to the β-coronavirus family and causes various problems such as acute respiratory distress syndrome and has resulted in a global pandemic. Though various medications have been under trial for combating COVID-19, specific medicine for treating COVID-19 is unavailable. Thus, the current situation urgently requires effective treatment modalities. Nigella sativa, a natural herb with reported antiviral activity and various pharmacological properties, has been selected in the present study to identify a therapeutic possibility for treating COVID-19. Methods: The present work aimed to virtually screen the bioactive compounds of N. sativa based on the physicochemical properties and docking approach against two SARS-CoV-2 enzymes responsible for crucial functions: 3CLpro (Main protease) and NSP15 (Nonstructural protein 15 or exonuclease). However, simulation trajectory analyses for 100ns were accomplished by using the YASARA STRUCTURE tool based on the AMBER14 force field with 400 snapshots every 250ps. RMSD and RMSF plots were successfully obtained for each target. Results: The results of molecular docking have shown higher binding energy of dithymoquinone (DTQ), a compound of N. sativa against 3CLpro and Nsp15, i.e., −8.56 kcal/mol and −8.31 kcal/mol, respectively. Further, the dynamic simulation has shown good stability of DTQ against both the targeted enzymes. In addition, physicochemical evaluation and toxicity assessment also revealed that DTQ obeyed the Lipinski rule and did not have any toxic side effects. Importantly, DTQ was much better in every aspect among the 13 N. sativa compounds and 2 control compounds tested. Conclusions: The results predicted that DTQ is a potent therapeutic molecule that could dual-target both 3CLpro and NSP15 for anti-COVID therapy.
... Dithymoquinone, a dimer of thymoquinone, also known as nigellone, exhibited higher binding affinity to both ACE-2 and S protein compared to chloroquine [20,28,29]. The great solubility and gut absorption of nigellone make it a potent lead structure for the future development of efficient antiviral derivatives [32]. Two other black seed phytocon-stituents known as nigellidine (an alkaloid) and α-hederin (a saponin) exhibited higher affinity against Mpro/3CL pro compared to various clinically approved drugs such as chloroquine, hydroxychloroquine, and favipiravir [18,33,34]. ...
Article
Full-text available
Background Since the beginning of medical history, plants have been exemplary sources of a variety of pharmacological compounds that are still used in modern medication. Respiratory infections are a serious and persistent global health problem, most acute and chronic respiratory infections are caused by viruses, whose ability to rapidly mutate may result in epidemics and pandemics, as seen recently with MERS-COV (2012) and SARS-COV-2 (2019), the latter causing coronavirus disease 2019 (COVID-19). Methods Highlight the tremendous benefits of plants that have been widely used as dietary supplements or traditional treatment for various respiratory infections, with a focus on the most effective constituents and studies that revealed their activities against COVID-19. Results Several traditional plants and their phytoconstituents have shown activity against respiratory viruses, including SARS-COV-2. The presented plants are Nigella sativa, Punica granatum, Panax ginseng, Withania somnifera, Glycyrrhiza glabra, Curcuma longa, Zingiber officinale, Camellia sinensis, Echinacea purpurea, Strobilanthes cusia, Stephania tetrandra, and genus Sambucus. Conclusion The data discussed in this review can encourage carrying out in-vivo studies that may help to the discovery of herbal leads that can be feasibly used to alleviate, prevent or treat COVID-19 infection.
Article
Full-text available
Nigella sativa has been used as traditional medicine for centuries. The crude oil and thymoquinone (TQ) extracted from its seeds and oil are effective against many diseases like cancer, cardiovascular complications, diabetes, asthma, kidney disease etc. It is effective against cancer in blood system, lung, kidney, liver, prostate, breast, cervix, skin with much safety. The molecular mechanisms behind its anticancer role is still not clearly understood, however, some studies showed that TQ has antioxidant role and improves body’s defense system, induces apoptosis and controls Akt pathway. Although the anti-cancer activity of N. sativa components was recognized thousands of years ago but proper scientific research with this important traditional medicine is a history of last 2~3 decades. There are not so many research works done with this important traditional medicine and very few reports exist in the scientific database. In this article, we have summarized the actions of TQ and crude oil of N. sativa against different cancers with their molecular mechanisms. Key words: Traditional medicine, Nigella sativa, Thymoquinone, Antioxidant, Anti-cancer mechanism doi: 10.4314/ajtcam.v8i5S.10
Article
Full-text available
To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
Article
Full-text available
Aims/hypothesis Metabolomics has provided new insight into diabetes risk assessment. In this study we characterised the human serum metabolic profiles of participants in the Singapore Chinese Health Study cohort to identify metabolic signatures associated with an increased risk of type 2 diabetes. Methods In this nested case–control study, baseline serum metabolite profiles were measured using LC-MS and GC-MS during a 6-year follow-up of 197 individuals with type 2 diabetes but without a history of cardiovascular disease or cancer before diabetes diagnosis, and 197 healthy controls matched by age, sex and date of blood collection. Results A total of 51 differential metabolites were identified between cases and controls. Of these, 35 were significantly associated with diabetes risk in the multivariate analysis after false discovery rate adjustment, such as increased branched-chain amino acids (leucine, isoleucine and valine), non-esterified fatty acids (palmitic acid, stearic acid, oleic acid and linoleic acid) and lysophosphatidylinositol (LPI) species (16:1, 18:1, 18:2, 20:3, 20:4 and 22:6). A combination of six metabolites including proline, glycerol, aminomalonic acid, LPI (16:1), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid and urea showed the potential to predict type 2 diabetes in at-risk individuals with high baseline HbA1c levels (≥6.5% [47.5 mmol/mol]) with an AUC of 0.935. Combined lysophosphatidylglycerol (LPG) (12:0) and LPI (16:1) also showed the potential to predict type 2 diabetes in individuals with normal baseline HbA1c levels (<6.5% [47.5 mmol/mol]; AUC = 0.781). Conclusions/interpretation Our findings show that branched-chain amino acids and NEFA are potent predictors of diabetes development in Chinese adults. Our results also indicate the potential of lysophospholipids for predicting diabetes.
Article
Full-text available
We aimed to investigate the change of serum metabolomics in response to n-3 fatty acid supplements in Chinese patients with type 2 diabetes (T2D). In a double-blind parallel randomised controlled trial, 59 Chinese T2D patients were randomised to receive either fish oil (FO), flaxseed oil (FSO) or corn oil capsules (CO, served as a control group) and followed up for 180 days. An additional 17 healthy non-T2D participants were recruited at baseline for cross-sectional comparison between cases and non-cases. A total of 296 serum metabolites were measured among healthy controls and T2D patients before and after the intervention. Serum 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) (P-interaction = 1.8 × 10(-7)) was the most significant metabolite identified by repeated-measures ANOVA, followed by eicosapentaenoate (P-interaction = 4.6 × 10(-6)), 1-eicosapentaenoylglycerophosphocholine (P-interaction = 3.4 × 10(-4)), docosahexaenoate (P-interaction = 0.001), linolenate (n-3 or n-6, P-interaction = 0.005) and docosapentaenoate (n-3, P-interaction = 0.021). CMPF level was lower in T2D patients than in the healthy controls (P = 0.014) and it was significantly increased in the FO compared with CO group (P = 1.17 × 10(-7)). Furthermore, change of CMPF during the intervention was negatively correlated with change of serum triglycerides (P = 0.016). In conclusion, furan fatty acid metabolite CMPF was the strongest biomarker of fish oil intake. The association of CMPF with metabolic markers warrants further investigation.
Article
Full-text available
Nigella sativa (NS) (Ranunculaceae family) is generally utilized as a therapeutic plant all over the world. The seeds of the plant have a long history of use in different frameworks of medicines and food. In Islamic literature, it is considered as one of the greatest forms of therapeutics. It has been widely used to treat nervous system diseases such as memory impairment, epilepsy, neurotoxicity, pain, etc. Additionally, this is uncovered that the majority of therapeutic properties of this plant are due to the presence of thymoquinone (TQ) which is a major bioactive component of the essential oil. Pharmacological studies have been done to evaluate the effects of NS on the central nervous system (CNS). The present review is an effort to provide a detailed scientific literature survey about pharmacological activities of the plant on nervous system. Our literature review showed that NS and its components can be considered as promising agents in the treatment of nervous system disorders.
Article
Full-text available
Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.
Article
Full-text available
Nigella sativa (N. sativa) seed, commonly known as ‘Black Seed’ in English and ‘Al-Habba Al-Sauda’ in Arabic, had been frequently used as a folk medicine for a large number of diseases since ancient times. N. sativa seed, its oil, various extracts and active components are reported to possess very useful pharmacological effects to include: immune stimulation, anti-inflammatory, antioxidant, anticancer, hypoglycemic, antihypertensive, anti-asthmatic, antimicrobial and anti-parasitic, etc. Some authors have reviewed these pharmacological activities in general but their neuropsychiatric effects are not separately and adequately described. The literature search has revealed a lot of publications pertaining to the actions of N. sativa in neurological and psychiatric problems, e.g., the control of pain, epilepsy, Parkinsonism, anxiety and drug dependence, as well as improvement of learning and memory, alertness, elevation of mood and feeling of good health, etc. Besides, because of its antioxidant, anti-inflammatory and other useful actions, was shown to provide neuro-protection from spinal cord injury and prevent damage to brain cells from various nerve toxins in experimental animal models. Moreover, black seed showed promising prophylactic and therapeutic effects on murine toxoplasmosis and demonstrated excellent antimalarial activity against various Plasmodium species in in vivo experiments, including Plasmodium falciparum strains notorious for causing cerebral malaria. The present article is intended to briefly review the valuable efforts of scientists to investigate the pharmacological activities and therapeutic potential of this precious natural herb pertaining to the neuropsychiatric diseases. It is hoped that the present manuscript would be of particular interest to the neurologists and psychiatrists, and the information provided would also benefit general physicians, medical students and the community.
Article
Full-text available
Prediabetes, a state of mild glucose intolerance, can persist for years before a sudden decline in beta cell function and rapid deterioration to overt diabetes. The mechanism underlying this tipping point of beta cell dysfunction remains unknown. Here, the furan fatty acid metabolite CMPF was evaluated in a prospective cohort. Those who developed overt diabetes had a significant increase in CMPF over time, whereas prediabetics maintained chronically elevated levels, even up to 5 years before diagnosis. To evaluate the effect of increasing CMPF on diabetes progression, we used obese, insulin-resistant models of prediabetes. CMPF accelerated diabetes development by inducing metabolic remodeling, resulting in preferential utilization of fatty acids over glucose. This was associated with diminished glucose-stimulated insulin secretion, increased ROS formation, and accumulation of proinsulin, all characteristics of human diabetes. Thus, an increase in CMPF may represent the tipping point in diabetes development by accelerating beta cell dysfunction.
Article
Context: Gestational diabetes (GDM) arises in women in whom there is insufficient beta-cell compensation for the insulin resistance of late pregnancy. The mechanisms underlying both normal antepartum beta-cell adaptation and its aberrancy in GDM are unclear. Pre-clinical studies have suggested that the hormones prolactin and human placental lactogen (HPL) may stimulate beta-cell mass, while the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) has recently emerged as a potential negative regulator of beta-cell function. However, there has been limited study of these factors in humans. Objective: To systematically evaluate HPL, prolactin, and CMPF in relation to glucose homeostasis and beta-cell function in women with and without GDM Design/Setting/Participants: Three-hundred-and-ninety-five women underwent an oral glucose tolerance test (OGTT) in late pregnancy, enabling assessment of GDM status, glycemia (area-under-the-glucose-curve on OGTT (AUCglucose)), beta-cell function (Insulin Secretion-Sensitivity Index-2 (ISSI-2), insulinogenic index/HOMA-IR), insulin sensitivity/resistance (Matsuda index, HOMA-IR), and circulating HPL, prolactin and CMPF. Results: Serum concentrations of HPL, prolactin, and CMPF were similar between women with GDM (n=105) and women without GDM (n=290). However, on multiple linear regression analyses, CMPF emerged as a significant predictor of AUCglucose in women with GDM (t=4.75, p<0.0001) but not in their peers (p=0.60). Furthermore, CMPF independently predicted lower ISSI-2 (t=-2.28, p=0.02) and lower insulinogenic index/HOMA-IR (t=-2.22, p=0.03) in women with GDM but not in the non-GDM group (both p=0.93). Neither HPL nor prolactin was significantly associated with AUCglucose, beta-cell function, or insulin sensitivity. Conclusion: CMPF is a potential circulating determinant of beta-cell dysfunction and hyperglycemia in women with GDM.