Molecular docking studies of N-substituted 4-methoxy-6-oxo-1-aryl-pyridazine-3-carboxamide derivatives as potential modulators of glutamate receptors

Introduction: The virtual target-oriented screening is a necessary stage of modern drug-design. In the present study, the affinity of pyridazine derivatives for the most promising antiparkinsonian biotargets – I–III groups of metabotropic and ionotropic NMDA-glutamate receptors – was evaluated. Materials and methods: Docking of the studied ligands to the active sites of biotargets – mGluR5, mGluR3, mGluR8, NMDA GluN2B – was performed using AutoDockVina. Base of the preparation of ligands and proteins – AutoDockTools-1.5.6. A Discovery Studio Visualizer 2017/R2 was used to visualize the interpretation of the results. Results and discussion: A high degree of the affinity is predicted for group III of the metabotropic mGlu8 receptors – binding energy from -5.0 to -8.7 kcal/mol, compared to -6.1 kcal/mol of that of the reference drug (L-AP4), as well as for the ionotropic NMDA GluN2B receptors –binding energy from -8.7 to -11.6 kcal/mol, compared to -11.3 kcal/mol of that of ifenprodil. Conclusion: The prospects of the searching for glutamate receptor modulators in a number of n-substituted 4-methoxy-6-oxo-1-aryl-pyridazine-3-carboxamide derivatives are proved. Some aspects of the structure-affinity relationship are discussed.

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Molecular Docking Studies on the Anti-Fungal Activity of Allium Sativum (Garlic) Against Mucormycosis (Black Fungus) by BIOVIA Discovery Studio Visualizer 21.1.0.0

10.21203/rs.3.rs-888192/v1 ◽

2021 ◽

Author(s):

Shaweta Sharma ◽

Akhil Sharma ◽

Utsav Gupta

Keyword(s):

Binding Energy ◽

Hydrogen Bonds ◽

Docking Studies ◽

Binding Energies ◽

Inhibition Constant ◽

Beta Glucan ◽

Glucan Synthase ◽

Fungal Protein ◽

Discovery Studio ◽

Black Fungi

Abstract Background: The COVID-19 pandemic is a major concern. However, its association and rising cases of mucormycosis, also known as black fungus make the scenario even more troublesome. In addition, no specific medication against mucormycosis/black fungus makes things even worse.Objective: Garlic phytoconstituents have shown remarkable antifungal properties against various fungal species in various studies. Thus, the objective of the study was to check the potency of garlic phytoconstituents against the 1,3-beta-glucan synthase fungal protein using in-silico methods.Method: Auto Dock was used to evaluate selected garlic phytochemical molecules against 1,3-beta-glucan synthase fungal protein, and Discovery studio visualizer was used to create 3D and 2D interaction photos.Results: Five out of 9 phytoconstituents were found to form conventional hydrogen bonds, and only alliin formed the highest number of hydrogen bonds. However, the binding energy and inhibition constant of all nine phytoconstituents were determined. Interestingly, Z-ajoene showed the lowest binding energy of -5.07 kcal/mol and inhibition constant of 192.57µM.Conclusion: The results of our investigation suggested that garlic phytochemicals can have a good impact against black fungi, pertaining to the significant binding energies of phytoconstituents during blind docking. Specifically, Z-ajoene could be a good alternate against black fungi. However, detailed research is required to explore the antifungal activity of garlic against mucormycosis.

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De-novo Drug Design, Molecular Docking and In-Silico Molecular Prediction of AChEI Analogues through CADD Approaches as Anti-Alzheimer’s Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409915666190301124210 ◽

2020 ◽

Vol 16 (1) ◽

pp. 54-72 ◽

Cited By ~ 2

Author(s):

Surabhi Pandey ◽

B.K. Singh

Keyword(s):

Molecular Docking ◽

Drug Design ◽

Inhibitory Activity ◽

In Silico ◽

Active Sites ◽

De Novo ◽

Docking Studies ◽

Target Protein ◽

Design And Development ◽

Reference Drug

Background: There are over 44 million persons who suffer with Alzheimer’s disease (AD) worldwide, no existence of cure and only symptomatic treatments are available for it. The aim of this study is to evaluate the anti-Alzheimer potential of designed AChEI analogues using computer simulation docking studies. AChEIs are the most potential standards for treatment of AD, because they have proven efficacy. Among all AChEIs donepezil possesses lowest adverse effects, it can treat mildmoderate- severe AD and only once-daily dosing is required. Therefore, donepezil is recognized as a significant prototype for design and development of new drug molecule. Methods: In this study the Inhibitory potential of the design compounds on acetylcholinesterase enzyme has been evaluated. Docking studies has been performed which further analyzed by in-silico pharmacokinetic evaluation through pharmacopredicta after that Interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds. Results: As a result 26 compounds have been indicates better inhibitory activity on AChE enzyme and all the screening parameters have also been satisfied by all 26 compounds. From these 26 compounds, six compounds 17, 18, 24, 30, 36 and 56 are found to be the most potent inhibitors of this series by insilico study through INVENTUS v 1.1 software, having highest bio-affinities i.e. - 8.51, - 7.67, - 8.30, - 7.59, - 8.71 and -7.62 kcal/mol respectively, while the standard or reference drug donepezil had binding affinity of - 6.32 kcal/mol. Conclusion: Computer aided drug design approach has been playing an important role in the design and development of novel anti- AD drugs. With the help of structure based drug design some novel analogues of donepezil have been designed and the molecular docking studies with structure based ADME properties prediction studies is performed for prediction of AChE inhibitory activity. The binding mode of proposed compounds with target protein i.e. AChE has been evaluated and the resulting data from docking studies explains that all of the newly designed analogues had significantly high affinity towards target protein compared to donepezil as a reference ligand.

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Molecular Docking Studies of N-Acetyl Cysteine, Zinc Acetyl Cysteine and Niclosamide on SARS Cov 2 Protease and Its Comparison with Hydroxychloroquine

10.26434/chemrxiv.12161493.v1 ◽

2020 ◽

Author(s):

Roopa Guthappa

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Active Sites ◽

Antiviral Drug ◽

Docking Studies ◽

Binding Affinities ◽

Binding Interaction ◽

Molecular Docking Studies ◽

Main Protease ◽

Acetyl Cysteine

To Respected Sir/Madam Chemarxiv Respected Sir/Madam Sub: submission of preprint of article to Chemarxiv for online publication. I am herewith submitting the preprint of an article entitled “Molecular docking studies of N-acetyl cysteine, zinc acetyl cysteine and niclosamide on SARS Cov 2 protease and its comparison with hydroxychloroquine” for possible publication in “Chemarxiv”. In this article, we have evaluated the binding abilities of N-acetyl cysteine, zinc acetyl cysteine and niclosamide (antiviral drug) with SARS-COV-2 protease. All the four compounds investigated are effective and selectively bind to active sites of main protease. N-acetyl cysteine being a derivative of cysteine interacts with Cys-145, His-163, Gly-143 of COV-2 protease, zinc acetyl cysteine binds to Gly-143, Ser-144, Cys-145, Glu-166 of COV-2 protease and niclosamide bind to Glu-166, Cys-145, His 41 of main protease. The data has been compared with hydroxychloroquine which effectively binds to Cys-145, Glu-166, Arg-188. The binding affinities of N-acetyl cysteine, zinc-acetyl cysteine and niclosamide are -4.24, -4.29 and -7.5 kcal mol-1 while for hydroxychloroquine it is -6.66 kcal mol-1. Niclosamide with its lowest binding energy interacts with His-41 and Cys-145 which may be the first molecule to show such binding interaction. The results indicate that N-acetyl cysteine, zinc-acetyl cysteine and niclosamide can also be explored for the treatment for SARS COV-2 as an alternative for hydroxychloroquine. I hope that the manuscript will full fill the journal’s requirements and will get accepted for publication. Thanking you With regards Roopa Guthappa <a href="mailto:[email protected]">[email protected]</a>

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Molecular Docking Studies of N-Acetyl Cysteine, Zinc Acetyl Cysteine and Niclosamide on SARS Cov 2 Protease and Its Comparison with Hydroxychloroquine

10.26434/chemrxiv.12161493 ◽

2020 ◽

Author(s):

Roopa Guthappa

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Active Sites ◽

Antiviral Drug ◽

Docking Studies ◽

Binding Affinities ◽

Binding Interaction ◽

Molecular Docking Studies ◽

Main Protease ◽

Acetyl Cysteine

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Design, Synthesis, Antimicrobial Evaluation and Molecular Docking Studies of Some Novel Monoterpenoids Substituted Quinoxaline Thiosemicarbazide Derivatives

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2021.14.2.8 ◽

2021 ◽

Vol 14 (2) ◽

pp. 5424-5435

Author(s):

Bipin Bihari ◽

Girendra Kumar Gautam ◽

Akash Ved

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Active Sites ◽

Docking Studies ◽

Dilution Method ◽

Molecular Docking Studies ◽

Fungal Strains ◽

Antimicrobial Evaluation ◽

Thiosemicarbazide Derivatives ◽

Antibacterial And Antifungal

Owing to the increasingly serious problems caused by multidrug resistance in acquired infection pathogens, it has become an urgent need to develop new classes of antibiotics for overcoming the resistance. The present study aims to increase the antimicrobial activity of quinoxaline thiosemicarbazide derivatives by introducing a hydrophobic alkyl chain, an electron-releasing group in the ring, and substitution by some acyclic, cyclic and bicyclic monoterpenes and their antimicrobial evaluation against various strains with molecular docking studies. The lead molecule (1E, 4E)-1-(7-chloro-3-isopropyl- quinoxalin-2(1H)-ylidene) thiosemicarbazide was synthesized and condensed with various monoterpenes to synthesize different derivatives. The structures of compounds were confirmed through IR., NMR & mass spectroscopy. The synthesized derivatives were evaluated in vitro for antibacterial and antifungal activities against various strains using the agar dilution method. Molecular docking studies of the derivatives (Va– Vg) were performed to find out essential binding sites against target protein (PDB: 3 FAP, receptor: FKBP 12) using Autodock 4.2. The compounds Va, Vd, Vf & Vg exhibited potent antibacterial and antifungal activity. Among all these compounds Vd was found to exhibit more potent activity against gram +Ve, gram –Ve bacterial and fungal strains at MIC 0.19 μg/ml, 0.39μg/ml, and 1.56 μg/ml respectively. The docking studies of all the compounds exhibit potent binding energy, but the compound Vd exhibit interactive binding energy (-9.98 kcal/mol) to the active pockets of the receptor FKBP12. The compound Vd interacting with various active sites of amino acids of receptors like PHE128, TRP190, TYR26, VAL55, ILE56, PHE99, and TRP59. In terms of structure- activity relationship study it is revealed that the activity profile against bacterial and fungal strains was altered by the formation of monoterpenoid substituted (1E, 4E)-1-(7- chloro-3-isopropylquinoxalin-2(1H)-ylidene) thiosemicar- bazide derivatives. The study reveals that bicyclic monoterpenes substituted compounds exhibit greater activity than cyclic and acyclic. The molecular docking studies also showed that all the compounds exhibit good docking energy to bind and inhibit the FKBP12 receptor.

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Molecular Docking studies on the Anti-fungal activity of Allium sativum (Garlic) against Mucormycosis (black fungus) by BIOVIA discovery studio visualizer 21.1.0.0

Annals of Antivirals and Antiretrovirals ◽

10.17352/aaa.000013 ◽

2021 ◽

pp. 028-032

Author(s):

Sharma Shaweta ◽

Sharma Akhil ◽

Gupta Utsav

Keyword(s):

Binding Energy ◽

Hydrogen Bonds ◽

Docking Studies ◽

Binding Energies ◽

Inhibition Constant ◽

Beta Glucan ◽

Glucan Synthase ◽

Fungal Protein ◽

Discovery Studio ◽

Black Fungi

Background: The COVID-19 pandemic is a major concern. However, its association and rising cases of mucormycosis, also known as black fungus make the scenario even more troublesome. In addition, no specific medication against mucormycosis/black fungus makes things even worse. Objective: Garlic phytoconstituents have shown remarkable antifungal properties against various fungal species in various studies. Thus, the objective of the study was to check the potency of garlic phytoconstituents against the 1,3-beta-glucan synthase fungal protein using in-silico methods. Method: Auto Dock was used to evaluate selected garlic phytochemical molecules against 1,3-beta-glucan synthase fungal protein, and Discovery studio visualizer was used to create 3D and 2D interaction photos. Results: Five out of 9 phytoconstituents were found to form conventional hydrogen bonds, and only alliin formed the highest number of hydrogen bonds. However, the binding energy and inhibition constant of all nine phytoconstituents were determined. Interestingly, Z-ajoene showed the lowest binding energy of -5.07 kcal/mol and inhibition constant of 192.57µM. Conclusion: The results of our investigation suggested that garlic phytochemicals can have a good impact against black fungi, pertaining to the significant binding energies of phytoconstituents during blind docking. Specifically, Z-ajoene could be a good alternate against black fungi. However, detailed research is required to explore the antifungal activity of garlic against mucormycosis.

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In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro)

Herba Polonica ◽

10.2478/hepo-2021-0009 ◽

2021 ◽

Vol 67 (2) ◽

pp. 1-8

Author(s):

Tomasz M. Karpiński ◽

Marek Kwaśniewski ◽

Marcin Ożarowski ◽

Rahat Alam

Keyword(s):

Binding Energy ◽

Active Site ◽

In Silico ◽

Active Sites ◽

Data Bank ◽

Pharmacokinetic Parameters ◽

Discovery Studio ◽

Main Protease ◽

In Silico Studies ◽

Potential Inhibitors

Summary Introduction: The main protease (Mpro) and the papain-like protease (PLpro) are essential for the replication of SARS-CoV-2. Both proteases can be targets for drugs acting against SARS-CoV-2. Objective: This paper aims to investigate the in silico activity of nine xanthophylls as inhibitors of Mpro and PLpro. Methods: The structures of Mpro (PDB-ID: 6LU7) and PLpro (PDB-ID: 6W9C) were obtained from RCSB Protein Data Bank and developed with BIOVIA Discovery Studio. Active sites of proteins were performed using CASTp. For docking the PyRx was used. Pharmacokinetic parameters of ADMET were evaluated using SwissADME and pkCSM. Results: β-cryptoxanthin exhibited the highest binding energy: –7.4 kcal/mol in the active site of Mpro. In PLpro active site, the highest binding energy had canthaxanthin of –9.4 kcal/mol, astaxanthin –9.3 kcal/mol, flavoxanthin –9.2 kcal/mol and violaxanthin –9.2 kcal/mol. ADMET studies presented lower toxicity of xanthophylls in comparison to ritonavir and ivermectin. Conclusion: Our findings suggest that xanthophylls can be used as potential inhibitors against SARS-CoV-2 main protease and papain-like protease.

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A Molecular Docking Study against COVID-19 Protease with a Pomegranate Phyto-Constituents 'Urolithin' and Other Repurposing Drugs: From a Supplement to Ailment

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i1130545 ◽

2020 ◽

pp. 51-62

Author(s):

Varish Ahmad

Keyword(s):

Binding Energy ◽

Antimicrobial Agents ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Discovery Studio ◽

Urolithin A ◽

In Silico Study ◽

Drug Compounds ◽

Urolithin B

Aim: We conducted an in silico study on Urolithin and different antimicrobial agents targeting virus protease and peptidase. Methodology: The docking study was completed by using docking tools. Drug compounds and COVID-19 receptor molecules were prepared, docking was performed and interaction was visualized through Discovery Studio visualizer. Results: Urolithin A has interacted against peptidase (PDB ID:2GTB) with binding energy -6.93 kcal/mol and against protease (PDB ID:6LU7) with the binding energy -5.46 kcal/mol, while Urolithin B has interacted to peptidase (PDB ID:2GTB) with binding energy -6.74 kcal/mol and with protease it interacted with a binding energy -4.67 kcal/mol. The antimicrobial agent Ofloxacin was found to interact against protease (PDB ID:6LU7) with a binding energy -6.84 kcal/mol and against protease (PDB:6LU7) with a binding energy -8.00 kcal/mol. Conclusion: The most common interacting amino acids of target enzymes of the virus with studied drugs were His41, His164, Met165, Glu166, Gln189. From the docking studies, it is observed that Ofloxacin and Urolithin have the potential to inhibit the virus protease as well as peptidase significantly and these could prevent the entry of the virus to the inside of the host cell. Thus, further antiviral research on these antimicrobial agents and Urolithin could be helpful to control the COVID-19 disease.

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Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes

Current Drug Discovery Technologies ◽

10.2174/1570163815666181008165822 ◽

2020 ◽

Vol 17 (2) ◽

pp. 233-247

Author(s):

Krishna A. Gajjar ◽

Anuradha K. Gajjar

Keyword(s):

Molecular Docking ◽

Structural Information ◽

Docking Studies ◽

Structural Motif ◽

Roc Curve Analysis ◽

Ligand Complex ◽

Discovery Studio ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Pharmacophore Models

Background: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. Methods: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Results and Conclusion: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

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1'-methylspiro[indoline-3,4'-piperidine] Derivatives: Design, Synthesis, Molecular Docking and Anti-tumor Activity Studies

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201117150714 ◽

2020 ◽

Vol 17 ◽

Author(s):

Junjian Li ◽

Lianbao Ye ◽

Yuanyuan Wang ◽

Ying Liu ◽

Xiaobao Jin ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Active Sites ◽

Biological Activities ◽

Significant Inhibition ◽

Alkaline Condition ◽

Discovery Studio ◽

Hela Cell Lines ◽

Antiproliferative Activities

Background: Spirocyclic indoline compounds widely exist in numerous natural products with good biological activities and some drug molecules in many aspects. In recent years, it has attracted extensive attention as potent anti-tumor agents in the fields of pharmacology and chemistry. Objective: In this study, we focused on designing and synthesizing a set of novel 1'-H-spiro[indole-3,4'-piperidine] derivatives, which were evaluated by preliminary bioactivity experiment in vitro and molecular docking. Method: The key intermediate 1'-methylspiro[indoline-3,4'-piperidine] (B4) reacted with benzenesulfonyl chloride with different substituents under alkaline condition to obtain its sulfonyl derivatives (B5-B10). We evaluated their antiproliferative activities against A549, BEL-7402 and HeLa cells by MTT assay. We performed the CDOCKER module in Discovery Studio 2.5.5 software for molecular modeling of compound B5, and investigated the binding of compound B5 with the target proteins from PDB database. Results: The results indicated that compounds B4-B10 exhibited good antiproliferative activities against the above three types of cells, in which compound B5 with chloride atom as electron-withdrawing substituent on a phenyl ring showed the highest potency against BEL-7402 cells (IC50=30.03±0.43 μg/mL). By binging of the prominent bioactive compound B5 to CDK, c-Met, EGFR protein crystals, The binding energy of B5 with these three types receptors are -44.3583 kcal/mol, - 38.3292 kcal/mol, -33.3653 kcal/mol respectively. Conclusion: Six 1'-methylspiro[indoline-3,4'-piperidine] derivatives were synthesized and evaluated against BEL-7402, A- 549, HeLa cell lines. Compound B5 showed significant inhibition on BEL-7402 cell lines. Molecular docking revealed that B5 showed good affinity by the good fitting between B5 and these three targets with amino acid residues in active sites which encourage us to conduct further evaluation such as the kinase experiment.

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