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Natural phosphodiesterase 5 (PDE5) inhibitors: a computational approach


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In 1998, sildenafil was marketed as the first FDA-approved oral drug for the treatment of erectile dysfunction (ED). During the last two decades, the commercialization of other synthetic phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the rise of remedies based on natural molecules from different chemical classes (flavonoids, polyphenols and alkaloids in general). In this work, a set of in silico tools were applied to study a panel of 30 natural compounds claimed to be effective against ED in the scientific literature or in folk medicine. First, pharmacokinetic properties were analysed to exclude the compounds lacking in specific drug-like features. Estimated binding energy for PDE5 and selectivity towards other PDE isoforms were then considered to highlight some promising molecules. Finally, a detailed structural investigation of the interaction pattern with PDE in comparison with sildenafil was conducted for the best performing compound of the set.
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Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage:
Natural phosphodiesterase 5 (PDE5) inhibitors: a
computational approach
Alberto Ongaro, Giuseppe Zagotto, Maurizio Memo, Alessandra Gianoncelli
& Giovanni Ribaudo
To cite this article: Alberto Ongaro, Giuseppe Zagotto, Maurizio Memo, Alessandra Gianoncelli
& Giovanni Ribaudo (2019): Natural phosphodiesterase 5 (PDE5) inhibitors: a computational
approach, Natural Product Research, DOI: 10.1080/14786419.2019.1619726
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Published online: 29 May 2019.
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Natural phosphodiesterase 5 (PDE5) inhibitors:
a computational approach
Alberto Ongaro
, Giuseppe Zagotto
, Maurizio Memo
, Alessandra Gianoncelli
and Giovanni Ribaudo
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy;
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy
In 1998, sildenafil was marketed as the first FDA-approved oral
drug for the treatment of erectile dysfunction (ED). During the
last two decades, the commercialization of other synthetic
phosphodiesterase 5 (PDE5) inhibitors has been paralleled by the
rise of remedies based on natural molecules from different chem-
ical classes (flavonoids, polyphenols and alkaloids in general). In
this work, a set of in silico tools were applied to study a panel of
30 natural compounds claimed to be effective against ED in the
scientific literature or in folk medicine. First, pharmacokinetic
properties were analysed to exclude the compounds lacking in
specific drug-like features. Estimated binding energy for PDE5 and
selectivity towards other PDE isoforms were then considered to
highlight some promising molecules. Finally, a detailed structural
investigation of the interaction pattern with PDE in comparison
with sildenafil was conducted for the best performing compound
of the set.
Received 15 March 2019
Accepted 12 May 2019
PDE5; erectile dysfunction;
flavonoids; sildena-
fil; docking
CONTACT Giovanni Ribaudo Department of Pharmaceutical and Pharmacological
Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy
Supplemental data for this article can be accessed at
ß2019 Informa UK Limited, trading as Taylor & Francis Group
1. Introduction
Sildenafil was the first oral drug acting through the inhibition of phosphodiesterase 5
(PDE5) approved by Food and Drug Administration (FDA) for the treatment of erectile
dysfunction (ED) (Goldstein et al. 1998; Goldstein 2000; Yafi et al. 2018). PDE5 inhibi-
tors contrast the degradation of cGMP promoting the relaxation of penile smooth
muscle and are currently ranked in terms of potency and of selectivity with respect to
other PDEs, which differ in substrate specificity, kinetic properties and tissue distribu-
tion (Bischoff 2004; Ribaudo et al. 2016). Flushing, headache, dyspepsia back pain,
myalgia hearing loss, visual disturbances, priapism and, in some specific cases, melan-
oma emerged to be the most common adverse effects related to the use of PDE5
inhibitors, which to some extent are due to interference with other PDE isoforms
(especially 1, 3, 6 and 11, among 11 known families) and other molecular mechanisms
(Bischoff 2004; Yafi et al. 2018). The fruitful development of PDE5 inhibitors during the
last two decades was paralleled by the rise of alternative treatments based on natural
remedies, which are often perceived as safer.
2. Results and discussion
Several natural compounds belonging to different chemical classes were reported to
show activity against ED and, although other molecular mechanisms may be involved,
inhibitory properties towards PDE5 have been claimed (Pavan et al. 2015; Abusnina
and Lugnier 2017).
Previous in silico studies investigated the interaction of single classes of natural
molecules, mainly polyphenols, with PDE5 (Srivani et al. 2007; Chen 2009; Ribaudo
et al. 2017; Arya et al. 2018). Moreover, concerning computer-aided drug discovery
aimed at highlighting novel synthetic PDE5 inhibitors, T
ori et al. presented a com-
prehensive in silico approach, including screening physico-chemical parameters, 2D
similarity and 3D docking (T
ori et al. 2012).
In the present work, 8 PDE isoforms and a selection of 30 natural compounds from
different plants and belonging to various chemical classes, which were reported as
effective in vitro and in vivo against ED, were considered. Remedies from traditional
medicine and phytocomplexes that were recently re-studied from a more rational
point of view were also included. Among flavonoids, icariin, apigenin, luteolin, naringe-
nin, quercetin, osajin, pomiferin, scandenone, auriculasin, and kraussianones 2-5 were
selected (Pavan et al. 2015; Ribaudo et al. 2015; Abusnina and Lugnier 2017; Oboh
et al. 2017). Some polyphenols and, more specifically, organic acids, namely forskolin,
resveratrol, gallic acid, chlorogenic acid, caffeic acid, ellagic acid, xanthohumol, and
EGCG were chosen and introduced in the study (Pavan et al. 2015; Oboh et al. 2017).
In addition to these two major classes, other alkaloids and anthocyanidins, such as del-
phinidin, maca 2, osthol, ginsenoside Re, caffeine, yohimbine, berberine, macaridine
and tyramine were considered (West and Krychman 2015; Abusnina and Lugnier 2017;
Ribaudo et al. 2018)(Figure 1). Sildenafil was selected as the reference molecule
throughout the in silico routine.
First, the predicted pharmacokinetic properties of the natural molecules were calcu-
lated using Molinspiration Cheminformatics software (
According to the guidelines from the most recent reports on drug-likeness, com-
pounds with TPSA >140 Å
and/or MW >800 Da (chlorogenic acid, EGCG, ellagic
acid, ginsenoside Re and icariin) were not admitted to the second step of the study,
since their expected cellular permeability would be very limited (Petit et al. 2012;
Matsson and Kihlberg 2017). Description of the computed parameters, detailed results
and selection criteria are reported in the Supplementary Material (Table S1).
Concerning the docking studies, the PDE isoforms available in the RCSB Protein
Data Bank ( were considered, in order to provide a preliminary selectiv-
ity profile towards PDE5. Besides PDE5 (2H44), compounds were docked to PDE1
(5W6E), PDE2 (4JIB), PDE4 (1XOS), PDE6 (3JWQ), PDE7 (4PM0), PDE9 (3JSW) and PDE10
(5K9R) following the protocol described in the Supplementary Material. Results are
reported in Table 1.
Two major criteria were adopted to identify the most promising compounds. First,
taking the estimated DG value for sildenafil towards PDE5 as reference (10.1 kcal/
mol), the molecules showing better binding energy values were highlighted. Second,
the molecules with a selectivity ratio towards other PDE isoforms >1 were discarded
(see Table S2 in the Supplementary Material for values). Selectivity ratio was calculated
dividing estimated DG values for other PDE isoforms by DG values for PDE5 (2H44)
ıa et al. 2018). The intersection between the resulting sets provided the final
group of molecules showing most promising calculated pharmacokinetic properties,
binding energy values and selectivity for PDE5 among the original array of 30 natural
compounds. This set of tentative leads includes apigenin, berberine, delphinidin, kraus-
sianone 2, 3 and 4, luteolin, naringenin, osajin and xanthohumol. The docking protocol
was preliminary assessed by comparing the computed results with the experimental
data on PDE5 inhibition and PDE-related vasorelaxant effects of the compounds avail-
able in the literature (see Table S3 in the Supplementary Material). Even though IC
values are not available for all the studied compounds, according to the retrieved data
the protocol was effective in predicting the potential efficacy of luteolin, osajin and
Figure 1. Chemical structures of some of the studied compounds belonging to the major investi-
gated chemical classes.
delphinidin and in correctly identifying most of non-active compounds (such
as quercetin and pomiferin). Although, the prediction of the behaviour of naringenin
and xanthohumol was less accurate. The reliability of the docking setup was also
verified by running the same in silico experiment using vardenafil, tadalafil, avanafil
and structures from the Database of Useful Decoys: Enhancedas ligands (Huang
et al. 2006; Mysinger et al. 2012), which showed estimated DG values ranging in
the higher half of the overall set (Table S4 in the Supplementary Material). Moreover,
from the point of view of the interaction motif, the accuracy of the prediction was
verified by re-docking the co-crystallized ligand sildenafil to PDE5 (2H42), obtaining
a superimposition between computed and experimental poses (Figure S1 in the
Supplementary Material).
Among the highlighted set of potentially bioactive natural molecules, kraussianone
2(Figure 1) showed the best estimated binding energy towards PDE5 (-11.9 kcal/mol).
This compound is contained in Eriosema kraussianum, which is used in South African
traditional medicine and is claimed to be effective against ED by Zulu traditional
health practitioners. Moreover, the vasorelaxant effect of kraussianones was previously
evaluated in rat models in comparison with sildenafil (Ojewole et al. 2006).
Kraussianone 2 has a low molecular weight (420.46 Da) and promising calculated
pharmacokinetic properties (TPSA ¼100.13 Å
and volume ¼376.57 Å
, in line with
sildenafil). In a more detailed docking study, the 3D binding motif of kraussianone 2
with PDE5 was compared to that computed for sildenafil. The compounds bind
to the same site and, as can be observed from 3D models and 2D interaction maps
Table 1. Estimated DG values (kcal/mol) for the studied compounds towards PDE isoforms. PDB
ID is given in parentheses.
(3JSW) PDE10 (5K9R)
Apigenin 10.6 9.7 9.4 9.6 8.6 9.6 8.8 8.3
Auriculasin 8.6 10.1 9.6 10.5 10.7 10.1 10.1 9.1
Berberine 11.7 10.1 9.7 10.0 9.5 7.3 9.4 9.0
Caffeic acid 7.4 6.9 6.8 7.1 7.2 6.9 6.6 6.3
Caffeine 7.3 5.9 6.3 6.0 6.1 6.3 5.8 6.5
Delphinidin 10.7 9.6 9.7 9.6 8.8 9.4 9.1 8.5
Forskolin 6.8 6.9 7.9 6.8 7.5 6.2 7.3 7.7
Gallic acid 7.2 5.9 5.8 6.1 5.9 6.2 5.9 5.8
Kraussianone 2 11.9 9.9 9.8 9.9 9.8 9.4 11.7 10.3
Kraussianone 3 11.8 8.8 9.8 9.9 9.8 9.6 11.7 10.3
Kraussianone 4 11.5 9.3 10.3 10.3 9.8 9.2 10.8 10.0
Kraussianone 5 8.5 8.8 9.4 8.7 8.7 8.6 9.0 8.1
Luteolin 10.6 9.7 9.6 10.0 9.2 10.0 9.0 8.4
Maca 2 5.4 6.3 6.7 6.4 5.9 6.7 6.1 6.0
Macaridine 7.4 6.9 6.9 7.0 7.5 7.3 7.2 6.2
Naringenin 10.3 9.6 9.2 9.6 8.6 9.6 8.6 8.2
Osajin 11.4 9.2 9.6 9.9 10.7 10.0 11.0 9.1
Osthol 9.4 7.3 7.6 8.0 7.7 7.1 8.0 7.4
Pomiferin 8.5 8.8 9.6 9.8 11.0 9.8 11.6 9.2
Quercetin 10.1 9.8 9.6 9.4 9.7 10.3 8.9 8.4
Resveratrol 9.3 8.4 8.5 8.8 8.0 8.5 8.2 7.4
Scandenone 8.1 10.1 9.3 10.7 10.3 10.6 10.0 8.9
Tyramine 6.1 5.9 5.6 6.0 6.1 6.1 5.3 5.1
Xanthohumol 10.2 8.8 8.9 8.9 8.5 9.2 8.3 8.5
Yohimbine 9.1 9.4 9.8 10.7 9.3 10.5 9.8 8.6
Sildenafil 10.1 8.2 9.3 10.3 9.8 9.4 9.7 7.8
(Figures S2S7 in the Supplementary Material), kraussianone 2 and the synthetic PDE5
inhibitor share common interaction patterns, mainly interfering with the same lipo-
philic residues (Val782, Phe786, Phe820) and some of the hydrophilic (His613, Asn661).
3. Conclusions
Therapeutic activity and adverse effects are consequences of sophisticated and inter-
connected molecular mechanisms related to the effective concentration reached by
the compounds in plasma and in tissues, where the several isoforms of PDEs are vari-
ously expressed. Drug-likeness and selectivity profile remain pivotal features for natural
molecules claimed to be effective on ED through PDE5 inhibition. Among a heteroge-
neous array of molecules, a group of natural compounds with different chemical scaf-
folds, satisfying predicted pharmacokinetic properties and good predicted selectivity
for PDE5 were highlighted. Kraussianone 2 proved to be the most promising com-
pound of the set according to the evaluated parameters.
Disclosure statement
The authors declare no conflict of interest.
This work was supported by University of Padova and University of Brescia.
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... Berberine and its derivatives exhibited various pharmacological activities, [35][36][37][38][39][40] such as anti-Alzheimer, [41][42][43][44][45][46][47] anti-parkinson, [48][49][50] anticancer, [51][52][53][54][55][56] anti-diabetic, [57][58][59][60] anti-obesity, [61][62][63][64] anti-inflammatory, [65][66][67][68] anti-atherosclerotic, [69][70][71] anti-bacterial, 21,[72][73][74][75][76][77][78] anti-viral, [79][80][81][82] and cardiovascular actions, 83,84 such as anti-arrhythmic, 85,86 anti-hypertensive, 87,88 and hypolipidemic activity, 89 These potential biological activities of berberine and reported derivatives were attributed due to their ability to interact with various biological targets involved in the pathogenesis of various diseases as shown in Figure 1. Berberine act as an anti-Alzheimer agent via inhibition of cholinesterases. ...
... [41][42][43] prolyl oligopeptidase (POP, ) 44 , aggregation of aberrant proteins like amyloidbeta peptide (Aβ, ) 45 ,and inhibition of monoamine oxidase (MAO, ) 46,47 , while the anti-parkinson effect was induced by the inhibition of monoamine oxidase-B (MAO-B, 48,49) and phosphodiesterase. 50 The antitumor effect of berberine and derivatives on various cancer cells (such as uterine cancer HeLa, lymphocytic leukemia L1210, bladder cancer BIU-87 and T24, melanoma B16, hepatoma HepG2, etc.) was correlated with its ability to inhibit cell proliferation by inducing cell cycle arrest in G1, G2, S, G0/G1, G1/S and G2/M phase by regulating the expression of various proteins such as cyclin B1, cyclin D1, cyclin E, p53, p21, topoisomerase I and retinoblastoma protein (Rb) involved in the signaling pathways. [51][52][53] It also regulates cell apoptosis by activating caspases and cell autophagy by targeting AMPK/mTOR/ULK1 pathway. ...
... A T47D cell-based reporter assay was manifested for the evaluation of their inhibitory effect upon HIF-1 transcriptional activity, while the cytotoxic effect of the compounds was analyzed on human breast cancer cell line (MCF-7). The results of in vitro assay revealed that the compound 10a produced the highest inhibitory activity against HIF-1 transcription with IC 50 value of 0.74 µM and also emerged to be the most potent cytotoxic derivative against MCF-7 displaying IC 50 that the compounds displayed potent suppressive activities on hypoxiainduced expression of HIF-1α protein as compared to the parent berberine. 100 Wang et al. synthesized a series of 12-substituted berberine derivatives (11, 12, Figure 7) and evaluated their growth inhibition activity against a panel of human cancer lines, i.e.; HCT-8, Bel7402, A549 and HeLa. ...
In the last few decades, traditional natural products have been the center of attention for the scientific community and exploration of their therapeutic abilities is proceeding perpetually. Berberine, with remarkable therapeutic diversity, is a plant derived isoquinoline alkaloid which is widely used as a traditional medicine in China. Berberine has been tackled as a fascinating pharmacophore to make great contributions to the discovery and development of new therapeutic agents against variegated diseases. Despite its tremendous therapeutic potential, clinical utility of this alkaloid was significantly compromised due to undesirable pharmacokinetic properties. To overcome this limitation, several structural modifications were performed on this scaffold to improve its therapeutic efficacy. The collective efforts of the community have achieved the tremendous advancements, bringing berberine to clinical use and discovering new therapeutic opportunities by structural modifications on the berberine scaffold. In this review, recent advancements in the medicinal chemistry of berberine and its derivatives in the last few years (2016-2020) have been compiled to represent inclusive data associated with various biological activities of this alkaloid. The comprehensive structure-activity relationship studies along with molecular modelling and mechanistic studies have also been summarized. This article would be highly helpful for the scientific community to get better insight into medicinal research of berberine and become a compelling guide for the rational design of berberine based compounds.
... Xanthines, including caffeine and caffeine-derived compounds, such as synthetic derivatives, represent outstanding examples of alkaloids modulating many different biochemical pathways in humans ( Figure 2) [25,26]. Caffeine itself, found in Coffea arabica and C. canephora, has been referred to as a multi-target compound for decades, in light of its polypharmacological effects [26]. ...
... This mechanism may be involved in its neuroprotective and anti-inflammatory effects [26]. On the other hand, it has also been reported that caffeine can interfere with intracellular cAMP and cGMP levels by acting as a weak, non-specific reversible PDE inhibitor (IC50 = 500-1000 μM) [25,30]. On this basis, caffeine is defined as a "cognitive enhancer", and a role for this alkaloid in the modulation of cognitive decline in AD has been proposed. ...
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... Eventually, we carried out a preliminary computational study to investigate the binding mode to the same macromolecular target examined in vitro of two highly representative components of the polyphenolic fraction of N. tabacum leaves, namely, rutin and chlorogenic acid [12][13][14]. These compounds have been widely investigated for their multitarget activity [37][38][39][40]. Indeed, computational tools are nowadays widely used in the drug discovery workflow [41,42]. ...
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... Sildenafil is the first active ingredient used as a peroral DE disorder therapy, working through inhibition of Phosphodiesterase 5 (PDE5) approved by the Food and Drug Administration (FDA) for the treatment of DE (Ongaro et al., 2021). In this study, sildenafil functioned as a comparison ligand. ...
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... Furthermore, available literature data was integrated with novel computational experiments that were carried out to "fill the gaps" that emerged when the various experimental protocols were overviewed and dedicating more discussion space to these cases where CBD was not present in the in silico test routine. In general, original in silico experiments were performed on the targets previously proposed in the reviewed articles, comparing CBD with CBDA and D9-THC [84]. CBDA was introduced in the study to stress the relevance of the decarboxylation step, and to highlight that natural acid precursors may possess their peculiar activity profile. ...
... The involved biochemical mechanisms include stimulation of cAMP response element binding protein (CREB) and brain derived neurotropic factor (BDNF), as well as improved release of nitric oxide (NO) (Kumar et al., 2015). Besides applications connected with their peripherical role, in light of their localization also in brain, PDE4, PDE5 and PDE9 are among the most studied isoform in the context of drug discovery against neurodegeneration (Cameron et al., 2017;Ongaro et al., 2021;Ribaudo et al., 2015Ribaudo et al., , 2016Ribaudo et al., , 2020Ribaudo et al., , 2021a. In particular, PDE9 outstands since it is present in amygdala, cerebellum, cortex, hippocampus, hypothalamus, midbrain, olfactory bulb and striatum (Lakics et al., 2010), and it has been found to be highly expressed in the brain of AD patients (Kumar et al., 2015). ...
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... Its ability to increase erection in response to visual stimuli would result in complete and successful sexual relationships. [2] Sildenafil could be useful for men with ED at any age, race, and body mass index. It might be beneficial in patients with diabetes, ischemic heart diseases, peripheral vascular diseases, hypertension, depression, and kidney diseases. ...
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Purpose: Sildenafil is a phosphodiesterase Type 5 inhibitor, which is a powerful and effective therapy for male erectile dysfunction (ED) and enables to restore temporary ED. The aim of this study was to evaluate the effects of sildenafil on seminal parameters in male participants with idiopathic infertility. Materials and Methods: This randomized, double-blind, controlled cross-over clinical trial study was conducted on 79 participants who had been referred to urology clinics in Rasht. Participants were assigned to two Groups A (n = 40), and B (n = 39). In Phase I, participants in Group A received a pill of sildenafil (50 mg) and then received a pill of placebo after the washout period, and participants in Group B received a pill of placebo and then received a pill of sildenafil after the washout period. In Phase II, participants in Group A received a pill of placebo and then received a pill of sildenafil after the washout period; and participants in group B received sildenafil and then received a placebo after the washout period. Results: The mean age of patients was 34 ± 5 years. There was no significant difference in the mean sperm count before receiving the drug in all groups. Sperm count, motility, morphology, pH, viscosity, and liquefaction time of semen did not significantly change after receiving sildenafil in comparison to their corresponding placebo group (P > 0.05). Conclusion: Sildenafil did not change sperm parameters in treating infertile patients; sildenafil also had no positive effect on semen parameters.
Phosphodiesterase type 5 (PDE5) is a cyclic GMP (cGMP) specific protein. It hydrolyzes the phosphodiesterase linkage and catalyzes the conversion of cGMP to 5’ GMP, which controls different physiological activities of the body. PDE5 is associated with biomedical conditions like neurological disorders, pulmonary arterial hypertension, cardiomyopathy, cancer, erectile dysfunction, and lower urinary tract syndrome. Inhibition of PDE5 has now been proven pharmaceutically effective in a variety of therapeutic conditions. Avanafil, tadalafil, sildenafil, and vardenafil are the most commonly used PDE5 inhibitors (PDE5i) today which are often used for the management of erectile dysfunction, lower urinary tract syndromes, malignancy, and pulmonary arterial hypertension. However, these synthetic PDE5i come with a slew of negative effects. Some of the most common side effects include mild headaches, flushing, dyspepsia, altered color vision, back discomfort, priapism, melanoma, hypotension and dizziness, non-arteritic anterior ischemic optic neuropathy (NAION), and hearing loss. In light of the potential negative effects of this class of medications, there is a lot of room for new, selective PDE5 inhibitors to be discovered. We have found 25 plant botanical compounds effectively inhibiting PDE5 which might be useful in treating a variety of disorders with minimal or no adverse effects.
Background Phosphodiesterases (PDEs) are a wide group of enzymes with multiple therapeutic actions, including vasorelaxation, cardiotonic, antidepressant, anti-inflammatory, antithrombotic, anti-spasmolytic, memory-enhancing, and anti-asthmatic. PDEs with eleven subtypes from PDE-1 to PDE-11 typically catalyze the cleavage of the phosphodiester bond and, hence, degrades either cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Objective Several selective or non-selective inhibitors of the PDE subtypes are used clinically, i.e. sildenafil, rolipram, cysteine, etc. Recently, interest in plant-based pharmacologically bioactive compounds having potent PDEs inhibitory potential has increased. Purposely, extensive research has been carried out on natural products to explore new inhibitors of various PDEs. Therefore, this review summarizes the published data on natural PDEs inhibitors and their potential therapeutic applications. Methods For this purpose, natural compounds with PDE inhibitory potential have been surveyed through several databases, including PubMed, Web of Sciences (WoS), Scopus, and Google Scholar. Results According to a detailed literature survey, the most promising class of herbal compounds with PDE-inhibiting property has been found to belong to phenolics, including flavonoids (luteolin, kaempferol, icariin, etc.). Many other encouraging inhibitors from plants have also been identified, such as coumarins (23, 24) (licoarylcoumarin and glycocoumarin,), saponins ( agapanthussaponins), lignans (31, 33) [(±)-schizandrin and kobusin], terpenes (28, 29, 31) (perianradulcin A, quinovic acid, and ursolic acid), anthraquinones (18, 19) (emodin and chrysophanol), and alkaloids (Sanjoinine-D) (36). Conclusion In this review, studies have revealed the PDE-inhibitory potential of natural plant extracts and their bioactive constituents in treating various diseases; however, further clinical studies comprising synergistic use of different therapies (synthetic & natural) to acquire multi-targeted results might also be a promising option.
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An increasing occurrence of resistance in insect pests and high mammal toxicity exhibited by common pesticides increase the need for new alternative molecules. Among these alternatives, bioinsecticides are considered to be environmentally friendly and safer than synthetic insecticides. Particularly, plant extracts have shown great potential in laboratory conditions. However, the lack of studies that confirm their mechanisms of action diminishes their potential applications on a large scale. Previously, we have reported the insect growth regulator and insecticidal activities of secondary metabolites isolated from plants of the Calceolaria genus. Herein, we report an in silico study of compounds isolated from Calceolaria against acetylcholinesterase, prophenoloxidase, and ecdysone receptor. The molecular docking results are consistent with the previously reported experimental results, which were obtained during the bioevaluation of Calceolaria extracts. Among the compounds, phenylethanoid glycosides, such as verbascoside, exhibited good theoretical affinity to all the analyzed targets. In light of these results, we developed an index to evaluate potential multitarget insecticides based on docking scores.
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Understanding the molecular mode of action of natural product is a key step for developing drugs from them. In this regard, this study is aimed to understand the molecular-level interactions of chemical constituents of Clerodendrum colebrookianum Walp., with anti-hypertensive drug targets using computational approaches. The plant has ethno-medicinal importance for the treatment of hypertension and reported to show activity against anti-hypertensive drug targets-Rho-associated coiled-coil protein kinase (ROCK), angiotensin-converting enzyme, and phosphodiesterase 5 (PDE5). Docking studies showed that three chemical constituents (acteoside, martinoside, and osmanthuside β6) out of 21 reported from the plant to interact with the anti-hypertensive drug targets with good glide score. In addition, they formed H-bond interactions with the key residues Met156/Met157 of ROCK I/ROCK II and Gln817 of PDE5. Further, molecular dynamics (MD) simulation of protein-ligand complexes suggest that H-bond interactions between acteoside/osmanthuside β6 and Met156/Met157 (ROCK I/ROCK II), acteoside and Gln817 (PDE5) were stable. The present investigation suggests that the anti-hypertensive activity of the plant is due to the interaction of acteoside and osmanthuside β6 with ROCK and PDE5 drug targets. The identified molecular mode of binding of the plant constituents could help to design new drugs to treat hypertension.
Introduction: Phosphodiesterase type 5 inhibitors (PDE5Is) have demonstrated efficacy in the treatment of erectile dysfunction (ED). Although historically found to have limited drug-related adverse events, emerging data have suggested that PDE5Is might be associated with melanoma or recurrence of prostate cancer after radical prostatectomy. Aim: To summarize the literature on the safety of PDE5Is. Methods: A literature review was performed through PubMed from 1990 through 2016 regarding ED. Keywords used for the search were erectile dysfunction, phosphodiesterase type 5 inhibitors, sildenafil, vardenafil, tadalafil, avanafil, safety, side effects, and adverse events, among others. Main outcome measures: Visual, auditory, cardiovascular, renal, hepatic, priapic, and oncologic outcomes associated with the intake of PDE5Is for the treatment of ED, in addition to drug interactions, abuse, overdose, and the phenomenon of counterfeit medications. Results: PDE5Is are safe drugs for the management of ED. Although recent studies have shown an increased risk of non-arteritic ischemic optic neuropathy with PDE5Is, the magnitude of that risk is small. The possibility that PDE5Is cause sensorineural hearing loss remains uncertain. PDE5Is display a safe cardiovascular profile if used according to the Princeton III Consensus guidelines. There appears to be an association between PDE5I use and melanoma but the absence of a mechanism of causation raises doubt that the association is cause and effect. PDE5Is do not increase the risk of biochemical recurrence after prostate cancer management. PDE5I abuse and use of counterfeit medications present serious global health concerns. Conclusion: Current data strongly support the efficacy, tolerability, and overall safety of PDE5Is for the treatment of ED. PDE5Is probably cause a small increase in the risk of non-arteritic ischemic optic neuropathy. Evidence on increased rates of melanoma and prostate cancer recurrence is weak and controversial. PDE5Is should still be considered first-line therapy for the treatment of most etiologies of ED. Yafi FA, Sharlip ID, Becher EF. Update on the Safety of Phosphodiesterase Type 5 Inhibitors for the Treatment of Erectile Dysfunction. Sex Med Rev 2017;X:XXX-XXX.
Intracellular cyclic AMP and/or cyclic GMP are characterized in the 1960th. These second messengers, hydrolysed specifically by cyclic nucleotide phosphodiesterase (PDE), play a major role in intracellular signalling. Natural products have been a rich source of drug discovery, Theophylline and Methylxanthine originated from tea leaves used for asthma treatment, whereas, Papaverine, a natural isoquinolein originated from Papaver somniferum traditionally used in impotency, altogether as caffeine where firstly described as PDE-inhibiting compounds. Since that time, the knowledge in PDE field has been drastically increased, allowing the design and development of new therapeutic drugs acting against different pathologies in the nanomolar range. During this period some natural compounds have been identified as PDE inhibitors and used in that context to investigate their therapeutic potential effects. The aim of this literature review is to point out the reported data and demonstrating the contribution of natural characterized molecules as PDE inhibitors in various pathologies that can open new fields of research for drug discovery, notably in epigenetic regulation.
Parkinson’s disease (PD) is a neurodegenerative disorder bearing motor and nonmotor symptoms. The treatment today is symptomatical rather than preventive or curative and this leaves the field open for the search of both novel molecular targets and drug candidates. Interference with α-synuclein fibrillation, monoamine oxidase (MAO) inhibition, modulation of adenosine receptors and the inhibition of specific phosphodiesterase (PDE) isoforms are some of the currently pursued strategies. We synthesised and studied some semi-synthetic berberine derivatives using a set of in silico tools. We evaluated their drug-likeness and tested the compounds against a set of target proteins involved in the onset or progression of PD, with a particular attention to MAO-B. Preliminary in vitro assay on MAO-B confirmed our in silico predictions.
Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery.
Background: Anogeissus leiocarpus and Hunteria umbellata have been reportedly used in traditional medicine for the management of erectile dysfunction (ED). However, the scientific basis for their use has not been well established. Therefore, this study was designed to investigate the inhibitory effects of water extractable phytochemicals of H. umbellata and A. leiocarpus on phosphodiesterase-5 (PDE-5) and arginase as well as pro-oxidants induced lipid peroxidation in rat penile tissue. Methods: The effects of the extracts on important enzymes (PDE-5 and arginase) linked with ED and pro-oxidants (Fe2+ and sodium nitroprusside) induced lipid peroxidation were investigated. Also, radicals scavenging and metal chelating abilities were determined. In addition, phenolic contents were determined and characterized using HPLC. Results: The results showed that both extracts inhibited PDE-5 and arginase activities in a dose-dependent manner. Inhibitory property of A. leiocarpus (IC50 - 174.19 μg/mL) was significantly better (p<0.05) than that of H. umbellata (IC50 - 537.72 μg/mL) in PDE-5 assay. The extracts were potent inhibitors of arginase than PDE-5, and these extracts were equally potent in inhibiting arginase. Furthermore, Fe2+ and sodium nitroprusside caused a significant increase in malondialdehyde content; however, both extracts reduced malondialdehyde level in concentration-dependent manner. It is noteworthy that both extracts scavenged radicals (OH* and ABTS*) and chelated Fe2+. HPLC analysis revealed abundance of rutin, chlorogenic acid, gallic acid, caffeic acid, and quercetin, among others. Conclusions: The ability of the extracts to inhibit PDE-5, arginase and pro-oxidant induced lipid peroxidation, and chelate metal might suggest their folkloric use for the management of ED.
Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein–protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery.
While osajin and pomiferin are known for their anticancer, antibacterial and antidiabetic properties, scandenone and auriculasin have been proposed as anti-inflammatory and antinociceptive agents. Curiously, these two couples of molecules are, from a chemical point of view, structural isomers which can all be extracted from Maclura pomifera. Although previous works described, separately, the isolation in reasonable amounts of the sole osajin/pomiferin couple or of scandenone/auriculasin, we report the extraction and characterization using direct spectral and chromatographical comparison of the four compounds. 2D NMR allowed to unambiguously assign the correct structures to the isomers. The compounds were screened in silico against PDE5 and their interaction pattern with the protein was compared with that of icarisid II, a natural PDE5 inhibitor.
Background: Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. Objective: We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. Methods: We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. Results: The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. Conclusion: Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying.