Discovery of novel 5α-reductase type II inhibitors by pharmacophore modelling,virtual screening,molecular docking and molecular dynamics simulations

Benign prostatic hyperplasia (BPH) is caused by augmented levels of androgen dihydrotestosterone (DHT) which is involved in the growth of the prostate in humans. 5α-Reductase type II (5αR2) is an intracellular enzyme that catalyses the formation of DHT from testosterone; hence, the inhibition of 5αR2 has emerged as one of the most promising strategies for the treatment of BPH. In this study, a computational approach that integrates ligand-based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics (MD) simulations was adopted to discover novel 5αR2 inhibitors with less side effects. After validating by Fischer's randomisation and Güner–Henry test, the best quantitative pharmacophore model (Hypo1), consisting of two hydrogen-bond acceptors and three hydrophobic features, was subsequently used as a three-dimensional-query in virtual screening to identify potential hits from Maybridge and National Cancer Institute databases. These hits were further filtered by ADMET (absorption, distribution, metabolism, elimination and toxicology) and molecular docking experiments, and their binding stabilities were validated by 10-ns MD simulations. Finally, only one hit was identified as a potential lead based on higher predicted inhibitory activity to 5αR2 compared with the most active inhibitor (finasteride). Our results further suggest that this potential lead could easily be synthesised and has structural novelty, making it a promising candidate for treating BPH.     

Synthesis, β-glucuronidase inhibition and molecular docking studies of hybrid bisindole-thiosemicarbazides analogs

Hybrid bisindole-thiosemicarbazides analogs (1–18) were synthesized and screened for β-glucuronidase activity. All compounds showed varied degree of β-glucuronidase inhibitory potential when compared with standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.4 ± 1.25 μM). Compounds 4, 7, 9, 6, 5, 12, 17 and 18 showed exceptional β-glucuronidase inhibition with IC₅₀ values ranging from 0.1 to 5.7 μM. Compounds 1, 3, 8, 16, 13, 2 and 14 also showed better activities than standard with IC₅₀ values ranging from 7.12 to 15.0 μM. The remaining compounds 10, 11, and 15 showed good inhibitory potential with IC₅₀ values 33.2 ± 0.75, 21.4 ± 0.30 and 28.12 ± 0.25 μM respectively. Molecular docking studies were carried out to confirm the binding interaction of the compounds.     

Green synthesis,inhibition studies of yeast α-glucosidase and molecular docking of pyrazolylpyridazine amines

An efficient and environmentally benign simple fusion reaction of 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (1a) or 3-chloro-6-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)pyridazine (2a) with different aliphatic/aromatic amines have produced a series of novel pyrazolylpyridazine amines (4a–4c & 5a–5m). All compounds exhibited moderate in vitro yeast α-glucosidase inhibition except m-chloro derivative 5g, which was found potent inhibitor of this enzyme with IC₅₀ value of 19.27 ± 0.005 µM. The molecular docking further helped in understanding the structure activity relationship of these compounds including 5g.     

Synthesis of thiobarbituric acid derivatives: In vitro α-glucosidase inhibition and molecular docking studies

Synthesis, structure, and evaluation of in vitro α-glucosidase enzyme inhibition of a new class of diethylammonium salts of aryl substituted thiobarbituric acid is described. This protocol is straight, environmentally benign and efficient, involving Aldol-Michael addition reaction in one pot fashion. The 3D chemical structures of the synthesized compounds were assigned based on spectroscopic methods and X-ray single crystal diffraction analyses. All synthesized compounds 3a-3n were evaluated for their in vitro α-glucosidase enzyme inhibitory activity, whereas acarbose was used as the standard drug (IC₅₀ = 840 ± 1.73 µM). All tested compounds were found to possess varying degree of α-glucosidase enzyme inhibition activity with (IC₅₀ = 19.46 ± 1.84–415.8 ± 4.0 µM). Compound 3i (IC₅₀ = 19.4 ± 1.84 µM) exhibited the highest activity. To the best of knowledge this is the first report of the in vitro α-glucosidase enzyme inhibition by the diethylamonium salts of aryl substituted thiobarbituric acid. Furthermore, molecular docking studies of selected compounds were also performed to see interactions between active compounds and binding sites.     

Identification of novel PPARα/γ dual agonists by virtual screening,ADMET prediction and molecular dynamics simulations

PPARα and PPARγ have been the most widely studied Peroxisome proliferator-activated receptor (PPAR) subtypes due to their important roles in regulating glucose, lipids, and cholesterol metabolism. By combining the lowering serum triglyceride levels benefit of PPARα agonists (such as fibrates) with the glycemic advantages of the PPARγ agonists (such as TZD), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence, has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of virtual screening, ADMET prediction and molecular dynamics (MD) simulations techniques, one compound-ASN15761007 with high binding score, low toxicity were gained. It was observed by MD simulations that ASN15761007 not only possessed the same function as AZ242 did in activating PPARα and BRL did in activating PPARγ, but also had more favorable conformation for binding to the two receptors. Our results provided an approach to rapidly produce novel PPARα/γ dual agonists which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.     

Identification of chemically diverse, novel inhibitors of 17β-hydroxysteroid dehydrogenase type 3 and 5 by pharmacophore-based virtual screening

17β-Hydroxysteroid dehydrogenase type 3 and 5 (17β-HSD3 and 17β-HSD5) catalyze testosterone biosynthesis and thereby constitute therapeutic targets for androgen-related diseases or endocrine-disrupting chemicals. As a fast and efficient tool to identify potential ligands for 17βHSD3/5, ligand- and structure-based pharmacophore models for both enzymes were developed. The models were evaluated first by in silico screening of commercial compound databases and further experimentally validated by enzymatic efficacy tests of selected virtual hits. Among the 35 tested compounds, 11 novel inhibitors with distinct chemical scaffolds, e.g. sulfonamides and triazoles, and with different selectivity properties were discovered. Thereby, we provide several potential starting points for further 17β-HSD3 and 17β-HSD5 inhibitor development. Article from the Special issue on Targeted Inhibitors.     

3D-QSAR pharmacophore-based virtual screening,molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B–NS3 protease inhibitors

NS2B–NS3 protease has been identified to serve as lead drug design target due to its significant role in West Nile viral (WNV) and dengue virus (DENV) reproduction and replication. There are currently no approved chemotherapeutic drugs and effective vaccines to inhibit DENV and WNV infections. In this work, 3D-QSAR pharmacophore model has been developed to discover potential inhibitory candidates. Validation through Fischer’s model and decoy test indicate that the developed 3D pharmacophore model is highly predictive for DENV inhibitors, which was then employed to screen ZINC chemical library to obtain reasonable hits. Following ADMET filtering, 15 hits were subjected to further filter through molecular docking and CoMFA modeling. Finally, top three hits were identified as lead compounds or potential inhibitory candidates with IC₅₀ values of ～0.4637?µM and fitness of ～57.73. It is implied from CoMFA modeling that substituents at the side site of benzotriazole such as a p-nitro group (e.g. biphenyl head) and a carbonyl (e.g. carboxylate function) at the side site of furan or amino group may improve bioactivity of ZINC85645245, respectively. Molecular dynamics simulations (MDS) were performed to discover new interactions and reinforce the binding modes from docking for the hits also. The QSAR and MDS results obtained from this work should be useful in determining structural requirements for inhibitor development as well as in designing more potential inhibitors for NS2B–NS3 protease.     

Identification of new antimalarial leads by use of virtual screening against cytochrome bc₁

Cytochrome bc(1) is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new drugs. We screened in silico the ZINC and MOE databases, using ligand- and structure-based approaches, to identify new leads for development. The most active compound presented an IC(50) value against cultured P. falciparum of 2 μM and a docking pose consistent with its activity.     

Potent and novel 11β-HSD1 inhibitors identified from shape and docking based virtual screening

Several potent and novel 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC(50) values lower than 100 nM and the best one 3.7 nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11β-HSD1 over 11β-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11β-HSD1 inhibitors to protect against metabolic syndrome.     

Insights on inhibition of Plasmodium falciparum plasmepsin I by novel epoxyazadiradione derivatives – molecular docking and comparative molecular field analysis

In the present study, we have explored the anti-malarial potential of epoxyazadiradione, the natural entity extracted from the neem seed oil and its chemical derivatives, against Plasmodium falciparum. The Surflex dock analysis of 41 compounds against an indispensable target, plasmepsin I (PM-I) revealed that around 70% of the compounds are found to have good binding capacity with the consensus score (C-score) of 5 to 4 with few hydrogen bonds. To elucidate the major structural requirements, vital for binding with the plasmepsin enzyme and to develop the predictive models, three-dimentional quantitative structural activity relationship (3D-QSAR) – comparative molecular field analysis (CoMFA) was carried out using Sybyl X.0. Robust and predictive models were obtained with cross-validated correlation coefficient (q²) value of 0.967 and the non-cross-validated correlation coefficient (r²) value of 0.825, which were validated by an external test set with the predictive correlation coefficient r²_(pred) values of 0.773. Three zones were identified for substitution with bulky groups and one zone for substitution with non-bulky groups. Three positions favouring the electronegative group substitution and one for the electropositive group substitution were identified. The physicochemical properties of ligands with the highest C-score were studied.

Communicated by Ramaswamy H. Sarma     

Screening of potential lead molecules against prioritised targets of multi-drug-resistant-Acinetobacter baumannii – insights from molecular docking,molecular dynamic simulations and in vitro assays

Acinetobacter baumannii, an opportunistic pathogen, has become multi-drug resistant (MDR) to major classes of antibacterial and poses grave threat to public health. The current study focused to screen novel phytotherapeutics against prioritised targets of Acinetobacter baumannii by computational investigation. Fourteen potential drug targets were screened based on their functional role in various biosynthetic pathways and the 3D structures of 9 targets were retrieved from Protein Data Bank and others were computationally predicted. By extensive literature survey, 104 molecules from 48 herbal sources were screened and subjected to virtual screening. Ten clinical isolates of A. baumannii were tested for antibiotic susceptibility towards clinafloxacin, imipenem and polymyxin-E. Computational screening suggested that Ajmalicine ((19α)-16, 17-didehydro-19-methyloxayohimban-16-carboxylic acid methyl ester from Rauwolfia serpentina), Strictamin (Akuammilan-17-oic acid methyl ester from Alstonia scholaris) and Limonin (7, 16-dioxo-7, 16-dideoxylimondiol from Citrus sps) exhibited promising binding towards multiple drug targets of A. baumannii in comparison with the binding between standard drugs and their targets. Limonin displayed promising binding potential (binding energy ?9.8 kcal/mol) towards diaminopimelate epimerase (DapF) and UDP-N-acetylglucosamine 1-carboxyvinyltransferase (MurA). Ajmalicine and Strictamin demonstrated good binding potential (?9.5, ?8.5 kcal/mol, respectively) towards MurA and shikimate dehydrogenase (?7.8 kcal/mol). Molecular dynamic simulations further validated the docking results. In vitro assay suggested that the tested isolates exhibited resistance to clinafloxacin, imipenem and polymyxin-E and the herbal preparations (crude extract) demonstrated a significant antibacterial potential (p ≤ .05). The study suggests that the aforementioned lead candidates and targets can be used for structure-based drug screening towards MDR A. baumannii.     

Synthesis, α-glucosidase inhibition,and molecular docking studies of novel N-substituted hydrazide derivatives of atranorin as antidiabetic agents

A series of novel N-substituted hydrazide derivatives were synthesized by reacting atranorin, a compound with a natural depside structure (1), with a range of hydrazines. The natural product and 12 new analogues (2–13) were investigated for inhibition of α-glucosidase. The N-substituted hydrazide derivatives showed more potent inhibition than the original. The experimental results were confirmed by docking analysis. This study suggests that these compounds are promising molecules for diabetes therapy. Molecular dynamics simulations were carried out with compound 2 demonstrating the best docking model using Gromac during simulation up to 20 ns to explore the stability of the complex ligand-protein. Furthermore, the activity of all synthetic compounds 2–13 against a normal cell line HEK293, used for assessing their cytotoxicity, was evaluated.     

Synthesis, α-glucosidase inhibition and molecular docking study of coumarin based derivatives

We have synthesized seventeen Coumarin based derivatives (1–17), characterized by ¹HNMR, ¹³CNMR and EI-MS and evaluated for α-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding α-glucosidase inhibition with IC₅₀ values ranging between 1.10 ± 0.01 and 36.46 ± 0.70 μM when compared with the standard inhibitor acarbose having IC₅₀ value 39.45 ± 0.10 μM. The most potent derivative among the series is derivative 3 having IC₅₀ value 1.10 ± 0.01 μM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent’s on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.     

Interaction of prodigiosin with HSA and β-Lg: Spectroscopic and molecular docking studies

Human serum albumin (HSA) and bovine β-lactoglobulin (β-Lg) are both introduced as blood and oral carrier scaffolds with high affinity for a wide range of pharmaceutical compounds. Prodigiosin, a natural three pyrrolic compound produced by Serratia marcescens, exhibits many pharmaceutical properties associated with health benefits. In the present study, the interaction of prodigiosin with HSA and β-Lg was investigated using fluorescence spectroscopy, circular dichroism (CD) and computational docking. Prodigiosin interacts with the Sudlow’s site I of HSA and the calyx of β-Lg with association constant of 4.41 × 10⁴ and 1.99 × 10⁴ M⁻¹ to form 1:1 and 2:3 complexes at 300 K, respectively. The results indicated that binding of prodigiosin to HSA and β-Lg caused strong fluorescence quenching of both proteins through static quenching mechanism. Electrostatic and hydrophobic interactions are the major forces in the stability of PG–HSA complex with enthalpy- and entropy-driving mode, although the formation of prodigiosin–β-Lg complex is entropy-driven hydrophobic associations. CD spectra showed slight conformational changes in both proteins due to the binding of prodigiosin. Moreover, the ligand displacement assay, pH-dependent interaction and protein–ligand docking study confirmed that the prodigiosin binds to residues located in the subdomain IIA and IIIA of HSA and central calyx of β-Lg.     

3D-QSAR,molecular docking and molecular dynamics studies of a series of RORγt inhibitors

The discovery of clinically relevant inhibitors of retinoic acid receptor-related orphan receptor-gamma-t (RORγt) for autoimmune diseases therapy has proven to be a challenging task. In the present work, to find out the structural features required for the inhibitory activity, we show for the first time a three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations for a series of novel thiazole/thiophene ketone amides with inhibitory activity at the RORγt receptor. The optimum CoMFA and CoMSIA models, derived from ligand-based superimposition I, exhibit leave-one-out cross-validated correlation coefficient (R²_cv) of .859 and .805, respectively. Furthermore, the external predictive abilities of the models were evaluated by a test set, producing the predicted correlation coefficient (R²_pred) of .7317 and .7097, respectively. In addition, molecular docking analysis was applied to explore the binding modes between the inhibitors and the receptor. MD simulation and MM/PBSA method were also employed to study the stability and rationality of the derived conformations, and the binding free energies in detail. The QSAR models and the results of molecular docking, MD simulation, binding free energies corroborate well with each other and further provide insights regarding the development of novel RORγt inhibitors with better activity.     

Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives

In search of potent α-amylase inhibitor we have synthesized eighteen indole analogs (1–18), characterized by NMR and HR-EIMS and screened for α-amylase inhibitory activity. All analogs exhibited a variable degree of α-amylase inhibition with IC₅₀ values ranging between 2.031 ± 0.11 and 2.633 ± 0.05 μM when compared with standard acarbose having IC₅₀ values 1.927 ± 0.17 μM. All compounds showed good α-amylase inhibition. Compound 14 was found to be the most potent analog among the series. Structure-activity relationship has been established for all compounds mainly based on bringing about the difference of substituents on phenyl ring. To understand the binding interaction of the most active analogs molecular docking study was performed.     

CoMFA, HQSAR and molecular docking studies of butitaxel analogues with β-tubulin

Results from biochemical analyses for a series of 20 butitaxel analogues, paclitaxel and docetaxel were used to build two- and three-dimensional quantitative structure-activity relationship (QSAR) models in order to investigate the properties associated with microtubule assembly and stabilization. A comparative molecular field analysis (CoMFA) model was built using steric and electrostatic fields. The CoMFA model yielded an r² of 0.943 and a cross-validated r² (i.e. q²) of 0.376. Hologram quantitative structure-activity relationship (HQSAR) modeling of these same data generated an r² of 0.919 and a q² of 0.471. Contour maps used to visualize the steric and electrostatic contributions associated with activity or lack thereof were, as expected, localized to the varied position of the taxane system. Each analogue was docked successfully into a model of -tubulin derived from previously determined cryoelectron microscopy analyses of the tubulin / heterodimer. All analogues superimposed well with paclitaxel bound to the protein, as well as with each other. Defining the variable region of each structure as the ligand and docking it separately into the paclitaxel site revealed a modest correlation (r²=0.53) between activity and docking energy of all the compounds in the dataset. When only the butitaxel derivatives were considered, the correlation increased to 0.61. The mathematical models derived here provide information for the future development of taxanes.     

Indole acrylonitriles as potential anti-hyperglycemic agents: Synthesis, α-glucosidase inhibitory activity and molecular docking studies

One of the most prevailing metabolic disorder diabetes mellitus has become the global health issue that has to be addressed and cured. Different marketed drugs have been made available for the treatment of diabetes but there is still a need of introducing new therapeutic agents that are economical and have lesser or no side effects. The current study deals with the synthesis of indole acrylonitriles (3–23) and the evaluation of these compounds for their potential for α-glucosidase inhibition. The structures of these synthetic molecules were deduced by using different spectroscopic techniques. Acarbose (IC₅₀ = 2.91 ± 0.02 μM) was used as standard in this study and the synthetic molecules (3–23) have shown promising α-glucosidase inhibitory activity. Compounds 4, 8, 10, 11, 14, 18, and 21 displayed superior inhibition of α-glucosidase enzyme in the range of (IC₅₀ = 0.53 ± 0.01–1.36 ± 0.04 μM) as compared to the standard acarbose. Compound 10 (IC₅₀ = 0.53 ± 0.01 μM) was the most effective inhibitor of this library and displayed many folds enhanced activity in contrast to the standard. Molecular docking of synthetic compounds was performed to verify the binding interactions of ligand with the active site of enzyme. This study had identified a number of potential α-glucosidase inhibitors that can be used for further research to identify a potent therapeutic agent against diabetes.     

Identification of potential PKC inhibitors through pharmacophore designing, 3D-QSAR and molecular dynamics simulations targeting Alzheimer’s disease

Protein kinases are ubiquitously expressed as Serine/Threonine kinases, and play a crucial role in cellular activities. Protein kinases have evolved through stringent regulation mechanisms. Protein kinases are also involved in tauopathy, thus are important targets for developing Anti-Alzheimer’s disease compounds. Structures with an indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors for human protein kinase C, here we report the generation of four point 3D geometric featured pharmacophore model. In order to identify novel and potent PKCθ inhibitors, the pharmacophore model was screened against 80,000,00 compounds from various chemical databases such as., ZINC, SPEC, ASINEX, which resulted in 127 compound hits, and were taken for molecular docking filters (HTVS, XP docking). After in-depth analysis of binding patterns, induced fit docking (flexible) was employed for six compounds along with the cocrystallized inhibitor. Molecular docking study reveals that compound 6F found to be tight binder at the active site of PKCθ as compared to the cocrystal and has occupancy of 90 percentile. MM-GBSA also confirmed the potency of the compound 6F as better than cocrystal. Molecular dynamics results suggest that compound 6F showed good binding stability of active sites residues similar to cocrystal 7G compound. Present study corroborates the pharmacophore-based virtual screening, and finds the compound 6F as a potent Inhibitor of PKC, having therapeutic potential for Alzheimer’s disease. Worldwide, 46.8 million people are believed to be living with Alzheimer’s disease. When elderly population increases rapidly and neurodegenerative burden also increases in parallel, we project the findings from this study will be useful for drug developing efforts targeting Alzheimer’s disease.     

Rutin as promising drug for the treatment of Parkinson’s disease: an assessment of MAO-B inhibitory potential by docking,molecular dynamics and DFT studies

ABSTRACT

Inhibitors of monoamine oxidase (MAO)-B have been used for many years in the therapy of Parkinson’s disease (PD). Owing to the safety concerns of the currently used agents, the discovery of novel scaffolds is of considerable interest. MAO-B inhibitory potential of rutin, a flavonoid derived from natural sources, has been established in experimental findings. Hence, the current study seeks to examine the interactions between rutin and crystal structure of human MAO-B enzyme. Molecular docking calculations, as well as molecular dynamics simulations, were employed to investigate the binding mode and the stability of the rutin/MAO-B complex. Energies of highest occupied/lowest unoccupied molecular orbitals were computed through DFT studies and used to calculate electron affinity, hardness, chemical potential, electronegativity, and electrophilicity index in order to investigate the capability of these parameters to influence the ligand–receptor interactions. It was found that rutin traverses both the entrance cavity and the substrate cavity, forcing the Ile-199 ‘gate’ to rotate into its open conformation. It results in the fusion of the two cavities of the MAO-B binding site and directly leads to better binding interactions. Results of the current study can be used for lead modification and development of novel drugs for the treatment of PD.