Article

Inhibitory and in silico molecular docking of Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa phytochemical compounds on human α-glucosidases

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Abstract

Ethnopharmacological relevance: Herbal traditional medicine is used by millions of people in Africa for treatment of ailments such as diabetes mellitus, stomach disorders and respiratory diseases. Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa (X. stuhlmannii (Taub.)) is a medicinal plant used traditionally in Zimbabwe to treat type 2 diabetes mellitus (T2DM) and its complications. However, there is no scientific evidence to support its inhibitory effect against digestive enzymes (α-glucosidases) that are linked to high blood sugar in humans. Aim of the study: This work aims to investigate whether bioactive phytochemicals of crude X. stuhlmannii (Taub.) can scavenge free radicals and inhibit α-glucosidases in order to reduce blood sugar in humans. Materials and methods: Here we examined the free radical scavenging potential of crude aqueous, ethyl acetate and methanolic extracts of X. stuhlmannii (Taub.) using the diphenyl-2-picrylhydrazyl assay in vitro. Furthermore, we carried out in vitro inhibition of α-glucosidases (α-amylase and α-glucosidase) by the crude extracts using chromogenic 3,5-dinitrosalicylic acid and p-nitrophenyl-α-D-glucopyranoside substrates. We also used molecular docking approaches (Autodock Vina) to screen for bioactive phytochemical compounds targeting the digestive enzymes. Results: Our results showed that phytochemicals in X. stuhlmannii (Taub.) aqueous, ethyl acetate and methanolic extracts scavenged free radicals with IC50 values ranging from 0.002 to 0.013 μg/mL. Furthermore, crude aqueous, ethyl acetate and methanolic extracts significantly inhibited α-amylase and α-glucosidase with IC50 values of 10.5–29.5 μg/mL (versus 54.1 ± 0.7 μg/mL for acarbose) and 8.8–49.5 μg/mL (versus 161.4 ± 1.8 μg/ mL for acarbose), respectively. In silico molecular docking findings and pharmacokinetic predictions showed that myricetin is likely a novel plant-derived α-glucosidase inhibitor. Conclusion: Collectively, our findings suggest pharmacological targeting of digestive enzymes by X. stuhlmannii (Taub.) crude extracts may reduce blood sugar in humans with T2DM via inhibition of α-glucosidases.

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Background There has been an appreciable increase in the number of people in Africa with metabolic syndrome and Type 2 diabetes (T2DM) in recent years as a result of a number of factors. Factors include lifestyle changes, urbanisation, and the growing consumption of processed foods coupled with increasing levels of obesity. Currently there are 19 million adults in Africa with diabetes, mainly T2DM (95%), estimated to grow to 47 million people by 2045 unless controlled. This has a considerable impact on morbidity, mortality and costs in the region. There are a number of issues to address to reduce the impact of T2DM including improving detection rates and current access to services alongside addressing issues of adherence to prescribed medicines. There are also high rates of co-morbidities with infectious diseases such as HIV and tuberculosis in patients in Africa with T2DM that require attention. Objective Document ongoing activities across Africa to improve the care of patients with T2DM especially around issues of identification, access, and adherence to changing lifestyles and prescribed medicines. In addition, discussing potential ways forward to improve the care of patients with T2DM based on ongoing activities and experiences including addressing key issues associated with co-morbidities with infectious diseases. Our Approach Contextualise the findings from a wide range of publications including internet based publications of national approaches coupled with input from senior level government, academic and other professionals from across Africa to provide future guidance. Ongoing Activities A number of African countries are actively instigating programmes to improve the care of patients with T2DM starting with improved diagnosis. This recognises the growing burden of non-communicable diseases across Africa, which has been neglected in the past. Planned activities include programmes to improve detection rates and address key issues with diet and lifestyle changes, alongside improving monitoring of care and activities to enhance adherence to prescribed medicines. In addition, addressing potential complexities involving diabetes patients with infectious disease co-morbidities. It is too early to fully assess the impact of such activities, Conclusion There are a number of ongoing activities across Africa to improve the management of patients with diabetes including co-morbidities. However, more needs to be done considering the high and growing burden of T2DM in Africa. Ongoing research will help further benefit resource allocation and subsequent care.
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Background Different plant parts of Roylea cinerea (D. Don) Baill. (Lamiaceae), Clematis grata Wall. (Ranunculaceae), Cornus capitata Wall. (Cornaceae) are traditionally used in the management of diabetes and various other diseases. Method The air-dried plant parts from different plants were coarsely powdered and macerated in methanol to obtain their crude extracts. The crude extracts were evaluated for their α-glucosidase inhibitory activity. On the basis of results obtained, the methanolic crude extract of Cornus capitata Wall. was further sequentially fractionated in hexane, diethyl ether, ethyl acetate, n-butanol. Fractions obtained were also evaluated for their α-glucosidase inhibitory potential. The kinetic study was performed using Lineweaver Burk plot to evaluate the type of inhibition. Furthermore, in silico analysis was also carried with active sites of the enzyme (PDB ID: 3WY1) using Autodock4. Results Among all the plant extracts, Cornus capitata extract showed maximum inhibitory activity. Therefore its methanolic extract was further fractionated with the help of different solvents and the maximum activity was shown by the ethyl acetate fraction (IC50 50 μg/mL). Kinetic analysis indicated that Vmax and Km were increased indicating a competitive type of inhibition. In docking studies, among different constituents known in this plant, betulinic acid showed minimum binding energy (− 10.21 kcal/mol). The kinetic and docking studies have strengthened the observation made in the present study regarding the α-glucosidase inhibitory activity of Cornus capitata. Conclusion The study provided partial evidence for pharmacological basis regarding clinical applications of Cornus capitata in the treatment of diabetes suggesting it to be a suitable candidate for the treatment of postprandial hyperglycemia.
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Myricetin (Myc) is one of the most important flavonoids in diet due to its abundance in foods with the highest antioxidant activity. The antioxidant activity of Myc was studied in cell-free and cell-based systems to evaluate the ROS protection efficiency of Myc. The studies were based on the assessment of reducing power of Myc according to ferric ion reduction and intracellular ROS level measurement by assaying the cellular fluorescence intensity using dichlorodihydrofluorescein (DCF) probe as an indicator for ROS in cells. Moreover, the antitoxic capability of Myc was assessed using MTT method. Data indicated that intracellular ROS are highly toxic and applying low concentration of Myc not only inhibited cellular ROS production but also was accompanying with the protection of cells against the highly toxic and the lethal effects of peroxide compounds. Because of strong correlation between cellular ROS and their cell toxic properties, the higher antioxidant potency of Myc in cell medium resulted in effectively blocking intracellular ROS and protecting cell death. This property is achieved by the help of high polar solubility and cell membrane permeability of Myc.
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Objective . Treating complications associated with diabetes and hypertension imposes significant costs on health care systems. This study estimated the hospitalization costs for inpatients in a public hospital in Zimbabwe. Methods . The study was retrospective and utilized secondary data from medical records. Total hospitalization costs were estimated using generalized linear models. Results . The median cost and interquartile range (IQR) for patients with diabetes, $994 (385–1553) mean $1319 (95% CI: 981–1657), was higher than patients with hypertension, $759 (494–1147) mean $914 (95% CI: 825–1003). Female patients aged below 65 years with diabetes had the highest estimated mean costs ($1467 (95% CI: 1177–1828)). Wound care had the highest estimated mean cost of all procedures, $2884 (95% CI: 2004–4149) for patients with diabetes and $2239 (95% CI: 1589–3156) for patients with hypertension. Age below 65 years, medical procedures (amputation, wound care, dialysis, and physiotherapy), the presence of two or more comorbidities, and being prescribed two or more drugs were associated with significantly higher hospitalization costs. Conclusion . Our estimated costs could be used to evaluate and improve current inpatient treatment and management of patients with diabetes and hypertension and determine the most cost-effective interventions to prevent complications and comorbidities.
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Growing evidence from animal studies supports the anti-diabetic properties of some dietary polyphenols, suggesting that dietary polyphenols could be one dietary therapy for the prevention and management of Type 2 diabetes. This review aims to address the potential mechanisms of action of dietary polyphenols in the regulation of glucose homeostasis and insulin sensitivity based on in vitro and in vivo studies, and to provide a comprehensive overview of the anti-diabetic effects of commonly consumed dietary polyphenols including polyphenol-rich mixed diets, tea and coffee, chocolate and cocoa, cinnamon, grape, pomegranate, red wine, berries and olive oil, with a focus on human clinical trials. Dietary polyphenols may inhibit α-amylase and α-glucosidase, inhibit glucose absorption in the intestine by sodium-dependent glucose transporter 1 (SGLT1), stimulate insulin secretion and reduce hepatic glucose output. Polyphenols may also enhance insulin-dependent glucose uptake, activate 5' adenosine monophosphate-activated protein kinase (AMPK), modify the microbiome and have anti-inflammatory effects. However, human epidemiological and intervention studies have shown inconsistent results. Further intervention studies are essential to clarify the conflicting findings and confirm or refute the anti-diabetic effects of dietary polyphenols.
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Virtual molecular screening is used to dock small-molecule libraries to a macromolecule in order to find lead compounds with desired biological function. This in silico method is well known for its application in computer-aided drug design. This chapter describes how to perform small-molecule virtual screening by docking with PyRx, which is open-source software with an intuitive user interface that runs on all major operating systems (Linux, Windows, and Mac OS). Specific steps for using PyRx, as well as considerations for data preparation, docking, and data analysis, are also described.
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The Tem tribe in the Central Region of Togo is a population with an extensive knowledge of medicinal plants. However, little is known about their medical practices, principally the use of plants in the management of diabetes mellitus (DM) and hypertension (HTN). The present study documented the indigenous medicinal plant utilization for the management of DM and HTN in the Togo Central Region. From March to October 2010, 55 traditional healers were interviewed about their knowledge on the use of plants for DM and HTN treatment. The results revealed that 35/55 (63.64%) healers had treated at least one case of DM and/or HTN. They highlighted the use of 64 species belonging to 31 families in the treatment of DM and/or HTN. The most used plants against diabetes were Psidium guajava L. (Myrtaceae), Khaya senegalensis A. Juss. (Meliaceae), Sarcocephalus latifolius (Sm.) E.A. Bruce (Rubiaceae), Annona muricata L. (Annonaceae), Bridelia ferruginea Benth. (Phyllanthaceae), and Securidaca longepedunculata Fresen. (Polygalacae), while Allium sativum L. (Liliaceae) and Parkia biglobosa Benth. (Fabaceae), followed by Khaya senegalensis A. Juss. (Meliaceae), Gardenia ternifolia Schumach. (Rubiaceae), and Persea americana Mill. (Lauraceae) were the most commonly cited as antihypertensive. The issue revealed that traditional healers of the above mentioned region have basic knowledge regarding herbal medicine for DM and HTN in comparison with previous published reports. Further pharmacological screening of the identified plants should be conducted to ascertain the effectiveness of these plants.
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An ethnobotanical study was conducted in the Wechiau Community Hippopotamus Sanctuary area in Ghana, through interviews and quadrate studies, to investigate the range and abundance of species used in the treatment of malaria. Forty-one species belonging to 17 families were encountered during the study. Of the 17 families studied Leguminosae and Anacardiaceae predominated in terms of number of species used to treat malaria. Eight plant species namely, Afraegle paniculata (Rutaceae), Haematostaphis barteri (Anacardiaceae), Indigo era pulchra (Leguminosae), Monanthotaxis sp. (Annonaceae), Ozoroa insignis (Anacardiaceae), Strychnos innocua (Loganiaceae), Strychnos spinosa (Loganiaceae) and Xeroderris stuhlmannii (Leguminosae) have not previously been documented for the treatment of malaria in Ghana. The results are discussed and recommendations made for future research to support the conservation and sustainable harvesting of the species reported to have medicinal properties.
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Six indigenous medicinal plants species, Agapanthus inapertus, Cheilanthes hirta, Crassula capitella, Eriospermum flagelliforme, Euphorbia clavarioides and Pelargonium alchemilloides are used traditionally in South Africa to treat wounds without scientific evidence as wound healing agents. Consequently, this study sought to investigate the antioxidant and anti-inflammatory activities of these plants species as a first step towards their validation as wound healing agents. The 2,2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), ferric reducing antioxidant power (FRAP), and β-carotene-linoleic acid model system (β-CLAMS) assays were used to test for antioxidant activity. The inhibition of the xanthine oxidase (XO), cyclooxygenase -2 (COX-2) and 15- lipoxygenase (15-LOX) as well as the extracts’ ability to preserve the cyclooxygenase-1 (COX-1) enzyme activity were used as anti-inflammatory models. Furthermore, the total phenolics, flavonoids and proanthocyanidins content were quantified using standard methods. Species, C. hirta displayed high flavonoid and proanthocyanidin content whilst C. capitella displayed high phenolic content, and good activity against the four used antioxidant models compared to standards, butylated hydroxytoluene and ascorbic acid. Majority of the extracts displayed significantly higher anti-xanthine oxidase activity, outperforming standard quercetin. The acetone extracts of A. inapertus (IC50 = 57.33 ± 0.30 µg/mL), E. flagelliforme (IC50 = 52.10 ± 0.98 µg/mL), P. alchemilloides (IC50 = 58.28 ± 0.94 µg/mL) and E. clavarioides water (IC50 = 50.53 ± 0.47 µg/mL) extract displayed moderate 15-LOX inhibition compared to standard, nordihydroguaiaretic acid (IC50 = 0.45 ± 0.01 µg/mL). The acetone extracts of C. capitella (IC50 = 3.16 ± 0.06 µg/mL), E. flagelliforme (IC50 = 1.13 ± 0.09 µg/mL), E. clavarioides (IC50 = 1.84 ± 0.18 µg/mL), P. alchemilloides (IC50 = 1.13 ± 0.14 µg/mL), and the E. clavarioides water extract (IC50 = 1.18 ± 0.11 µg/mL) displayed COX-2 inhibition comparable to that of standard, aspirin (IC50 = 1.11 ± 0.03 µg/mL). At some degree, all tested extracts preserved the activity of the COX-1 enzyme with the E. clavarioides acetone extract significantly preserving the activity of COX-1 (IC50 = 96.21 ± 0.18 µg/mL), compared to standard, aspirin (IC50 = 0.98 ± 0.06 µg/mL). The antioxidant and anti-inflammatory activities displayed by these medicinal plants support their application and beneficial effect in wounds healing and hold promising prospects as natural alternatives to the existing conventional treatments.
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Aims To provide global, regional, and country-level estimates of diabetes prevalence and health expenditures for 2021 and projections for 2045. Methods A total of 219 data sources meeting pre-established quality criteria reporting research conducted between 2005 and 2020 and representing 215 countries and territories were identified. For countries without data meeting quality criteria, estimates were extrapolated from countries with similar economies, ethnicity, geography and language. Logistic regression was used to generate smoothed age-specific diabetes prevalence estimates. Diabetes-related health expenditures were estimated using an attributable fraction method. The 2021 diabetes prevalence estimates were applied to population estimates for 2045 to project future prevalence. Results The global diabetes prevalence in 20–79 year olds in 2021 was estimated to be 10.5% (536.6 million people), rising to 12.2% (783.2 million) in 2045. Diabetes prevalence was similar in men and women and was highest in those aged 75–79 years. Prevalence (in 2021) was estimated to be higher in urban (12.1%) than rural (8.3%) areas, and in high-income (11.1%) compared to low-income countries (5.5%). The greatest relative increase in the prevalence of diabetes between 2021 and 2045 is expected to occur in middle-income countries (21.1%) compared to high- (12.2%) and low-income (11.9%) countries. Global diabetes-related health expenditures were estimated at 966 billion USD in 2021, and are projected to reach 1,054 billion USD by 2045. Conclusions Just over half a billion people are living with diabetes worldwide which means that over 10.5% of the world’s adult population now have this condition.
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α-Glucosidase inhibition of 11 flavonoids, including myricetins, quercetins and catechins were studied through initial reaction velocity, IC50 value, inhibition kinetics, fluorescence quenching and molecular docking. It was found that C4=O, C2=C3, 3-OH and 5’-OH were essential moieties for α-glucosidase inhibition of myricetin that was shown with the highest inhibitory activity. The trans-conformational catechins was shown with stronger inhibition effects than the cis-conformational ones. Further, gallocatechin was an uncompetitive inhibitor, while myricetin, myricetrin, quercetin and catechin were competitive ones. 3-OH and 5’-OH promoted myricetin to bind with the enzyme active site through hydrogen bondings. The presence of C4=O and C2=C3 increased electron delocalization in ring A-C for myricetin and quercetin, and this enhanced stability of π-conjugations with aromatic residues of amino acids. However, 5’-OH decreased the quenching effects because it limited π-conjugations of ring B with key fluorescent residues. Notably, for same flavonoid sort, the constants that indicate binding affinity of flavonoids to α-glucosidase, including reciprocal of competitive inhibition constant, fluorescence quenching constant and binding energy followed same order as the inhibitory activity, indicating that α-glucosidase inhibition of the flavonoids resulted from binding interactions between them, and that the methods above can be combined reasonably to characterize flavonoid-enzyme binding interactions.
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Herbal medicine use is common in rural communities of Zimbabwe since generic drugs are expensive and not readily available. In this work, we carried out phytochemical screening of secondary metabolites and used GC MS and tandem mass spectroscopy (LC MS/MS) to characterize Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa bark extracts. The activity of bark extracts on six bacterial strains were tested in vitro using the disc diffusion method. Qualitative screening of secondary metabolites confirmed the presence of alkaloids, flavonoids, terpenoids, steroids and polyphenols in the crude bark extracts. Methanol extracted more secondary metabolites compared to other solvents. The minimum inhibitory concentrations (MICs) values for the crude extracts on six bacterial strains ranged from 0.23–0.80 mg/mL. Antibacterial tests showed higher potency for crude bark extracts on E. Coli (MIC, 0.232 mg/mL) and lower potency on coliform (MIC, 0.798 mg/mL). LC-MS/MS analysis of various fractions confirmed the presence of twenty-eight phytochemicals whereas, twelve phytochemicals were identified using GC-MS. Both techniques confirmed the presence of ursolic acid, roburic acid, reticuline, rotenone and p-coumaric acid glucoside in hexane and methanol extracts. Our findings demonstrate that Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa contain many phytochemical compounds that have antibacterial activity. Some of these compounds in the bark extract possess antioxidant, antiviral, antitumor and anti-inflammatory properties. Thus, Xeroderris stuhlmannii (Taub.) Mendonca & E.P. Sousa barks can act as a useful herbal supplement for treatment of a number of diseases in rural communities. Future work will involve isolation of bioactive phytochemicals and their full characterization using LC MS/MS as well as testing their antioxidant, antidiabetic, anticancer properties and toxicity.
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Aims: To provide global estimates of diabetes prevalence for 2019 and projections for 2030 and 2045. Methods: A total of 255 high-quality data sources, published between 1990 and 2018 and representing 138 countries were identified. For countries without high quality in-country data, estimates were extrapolated from similar countries matched by economy, ethnicity, geography and language. Logistic regression was used to generate smoothed age-specific diabetes prevalence estimates (including previously undiagnosed diabetes) in adults aged 20-79 years. Results: The global diabetes prevalence in 2019 is estimated to be 9.3% (463 million people), rising to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. The prevalence is higher in urban (10.8%) than rural (7.2%) areas, and in high-income (10.4%) than low-income countries (4.0%). One in two (50.1%) people living with diabetes do not know that they have diabetes. The global prevalence of impaired glucose tolerance is estimated to be 7.5% (374 million) in 2019 and projected to reach 8.0% (454 million) by 2030 and 8.6% (548 million) by 2045. Conclusions: Just under half a billion people are living with diabetes worldwide and the number is projected to increase by 25% in 2030 and 51% in 2045.
Article
The cytochrome P450 (P450) enzymes first attracted interest because of their relevance to the metabolism of drugs, steroids, and carcinogens. Collectively, the 57 human P450s are involved in approximately three fourths of the metabolism of marketed drugs. Many of the steroid-oxidizing P450s have important roles in endocrinology. The roles of individual P450s can be predicted during drug development, and many drug–drug interactions are understood in the context of P450s. The human P450s involved in the metabolism of many carcinogens have been identified, and this information forms the basis for investigation into the human risk of these chemicals. Many questions still remain about the physiological roles of many human P450s, the relevance of the reactions they catalyze, and even the chemistry of some of the reactions. In this chapter, each of the 57 human P450s is discussed regarding current information about sites of expression, regulation, genetic variation, substrates and reactions, structures, inhibitors, and clinical issues.
Article
Background: The effect of in vivo treatment with ursolic acid (UA) on glycemia in hyperglycemic rats and its mechanism of action on muscle were studied. Methods: The UA effects on glycemia, glycogen, LDH, calcium and on insulin levels were evaluated after glucose tolerance curve. The β-cells were evaluated through the transmission electron microscopy. UA mechanism of action was studied on muscles through the glucose uptake with/without specific insulin signaling inhibitors. The nuclear effect of UA and the GLUT4 expression on muscle were studied using thymidine, GLUT4 immunocontent, immunofluorescence and RT-PCR. Results: UA presented a potent antihyperglycemic effect, increased insulin vesicle translocation, insulin secretion and augmented glycogen content. Also, UA stimulates the glucose uptake through the involvement of the classical insulin signaling related to the GLUT4 translocation to the plasma membrane as well as the GLUT4 synthesis. These were characterized by increasing the GLUT4 mRNA expression, the activation of DNA transcription, the expression of GLUT4 and its presence at plasma membrane. Also, the modulation of calcium, phospholipase C, protein kinase C and PKCaM II is mandatory for the full stimulatory effect of UA on glucose uptake. UA did not change the serum LDH and serum calcium balance. Conclusions: The antihyperglycemic role of UA is mediated through insulin secretion and insulinomimetic effect on glucose uptake, synthesis and translocation of GLUT4 by a mechanism of cross-talk between calcium and protein kinases. General significance: UA is a potential anti-diabetic agent with pharmacological properties for insulin resistance and diabetes therapy.
Article
It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.
Article
The increasing prevalence of diabetes has accelerated the search for new drugs derived from natural sources. To define the functional features of two such families of compounds, the flavonols and the ethyl caffeates, we have determined the high-resolution structures of representative inhibitors in complex with human pancreatic α-amylase. Myricetin binds at the active site and interacts directly with the catalytic residues despite its bulky planar nature. Notably, it reduces the normal conformational flexibility of the adjacent substrate binding cleft. In contrast, bound ethyl caffeate acts by disordering precisely those polypeptide chain segments that make up the active site binding cleft. It also operates from binding sites far removed from the active site, a property not observed in any other class of human α-amylase inhibitor studied to date. Given the current inadequacy of drugs directed at diabetes, the use of optimized flavonols and ethyl caffeates may present an alternative therapeutic route.
Article
Two household surveys undertaken in Zimbabwe between 1981 and 1983 revealed extensive use of indigenous plant remedies in the home-management of childhood diarrhoea and many adult illnesses. Names of the local plants, trees and shrubs are listed, together with the part of the plant used and the type of condition treated. The usage of medicinal plants underscores the need for further study of indigenous pharmacopoeias and the therapeutic properties of plants. The role of indigenous plant remedies within local health care systems is also worthy of closer investigation.
Article
A mechanistic study of the essential allosteric activation of human pancreatic alpha-amylase by chloride ion has been conducted by exploring a wide range of anion substitutions through kinetic and structural experiments. Surprisingly, kinetic studies indicate that the majority of these alternative anions can induce some level of enzymatic activity despite very different atomic geometries, sizes, and polyatomic natures. These data and subsequent structural studies attest to the remarkable plasticity of the chloride binding site, even though earlier structural studies of wild-type human pancreatic alpha-amylase suggested this site would likely be restricted to chloride binding. Notably, no apparent relationship is observed between anion binding affinity and relative activity, emphasizing the complexity of the relationship between chloride binding parameters and the activation mechanism that facilitates catalysis. Of the anions studied, particularly intriguing in terms of observed trends in substrate kinetics and their novel atomic compositions were the nitrite, nitrate, and azide anions, the latter of which was found to enhance the relative activity of human pancreatic alpha-amylase by nearly 5-fold. Structural studies have provided considerable insight into the nature of the interactions formed in the chloride binding site by the nitrite and nitrate anions. To probe the role such interactions play in allosteric activation, further structural analyses were conducted in the presence of acarbose, which served as a sensitive reporter molecule of the catalytic ability of these modified enzymes to carry out its expected rearrangement by human pancreatic alpha-amylase. These studies show that the largest anion of this group, nitrate, can comfortably fit in the chloride binding pocket, making all the necessary hydrogen bonds. Further, this anion has nearly the same ability to activate human pancreatic alpha-amylase and leads to the production of the same acarbose product. In contrast, while nitrite considerably boosts the relative activity of human pancreatic alpha-amylase, its presence leads to changes in the electrostatic environment and active site conformations that substantially modify catalytic parameters and produce a novel acarbose rearrangement product. In particular, nitrite-substituted human pancreatic alpha-amylase demonstrates the unique ability to cleave acarbose into its acarviosine and maltose parts and carry out a previously unseen product elongation. In a completely unexpected turn of events, structural studies show that in azide-bound human pancreatic alpha-amylase, the normally resident chloride ion is retained in its binding site and an azide anion is found bound in an embedded side pocket in the substrate binding cleft. These results clearly indicate that azide enzymatic activation occurs via a mechanism distinct from that of the nitrite and nitrate anions.
AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading
  • Trott
Trott, O., Olson, A.J., 2009. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 455-461. https://doi.org/10.1002/jcc.21334.