Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike Receptor-Binding Domain Bound with ACE2 COVID19 Target Proteins: A Virtual Drug Repurposing Study

In this virtual drug repurposing study, we used 7922 FDA approved drugs and compounds in clinical investigation from NPC database. Both apo and holo forms of SARS-CoV-2 Main Protease as well as Spike Protein/ACE2 were used for virtual screening. Initially, docking was performed for these compounds at target binding sites. The compounds were then sorted according to their docking scores which represent binding energies. The first 100 compounds from each docking simulations were initially subjected to short (10 ns) MD simulations (in total 300 ligand-bound complexes), and average binding energies during MD simulations were calculated using the MM/GBSA method. Then, the selected promising hit compounds based on average MM/GBSA scores were used in long (100-ns and 500-ns) MD simulations. In total around 15 µs MD simulations were performed in this study. Both docking and MD simulations binding free energy calculations showed that holo form of the target protein is more appropriate choice for virtual drug screening studies. These numerical calculations have shown that the following 8 compounds can be considered as SARS-CoV-2 Main Protease inhibitors: Pimelautide, Rotigaptide, Telinavir, Ritonavir, Pinokalant, Terlakiren, Cefotiam and Cefpiramide. In addition, following 5 compounds were identified as potential SARS-CoV-2 ACE-2/Spike protein domain inhibitors: Denopamine, Bometolol, Naminterol, Rotigaptide and Benzquercin. These compounds can be clinically tested and if the simulation results validated, they may be considered to be used as treatment for COVID-19.

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Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study

10.26434/chemrxiv.12032712.v1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Serdar Durdagi ◽

Busecan Aksoydan ◽

Berna Dogan ◽

Kader Sahin ◽

Aida Shahraki

Keyword(s):

Virtual Screening ◽

Clinical Investigation ◽

Drug Repurposing ◽

Md Simulations ◽

Binding Energies ◽

New Drugs ◽

Docking Simulations ◽

New Drug ◽

Main Protease ◽

Glide Docking

<div>There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged preclinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against</div><div>COVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study. Both apo and holo forms of target protein COVID-19 main proteases were used in virtual screening. Target proteins were retrieved from protein data bank (PDB IDs, 6M03 and 6LU7). Standard Precision (SP) protocol of Glide docking program of Maestro was used in docking. Compounds were then ranked based on their docking scores that represents binding energies. Top-30 compounds from each docking simulations were considered initially in short (10-ns) molecular dynamics (MD) simulations and their average binding energies using collected 1000 trajectories throughout the MD simulations were calculated by Molecular Mechanics Generalized Born Surface Area (MM/GBSA) method. Selected promising hit compounds based on average MM/GBSA scores were then used in long (100-ns) MD simulations. These numerical calculations showed that the following 6 compounds can be considered as COVID-19 Main Protease inhibitors: Lasinavir, Brecanavir, Telinavir, Rotigaptide, 1,3-Bis-(2-ethoxycarbonylchromon-5-yloxy)-2-(lysyloxy)propane and Pimelautide.</div>

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Possibility of HIV-1 Protease Inhibitors-Clinical Trial Drugs as Repurposed Drugs for SARSCoV-2 Main Protease: A Molecular Docking, Molecular Dynamics and Binding Free Energy Simulation Study

10.26434/chemrxiv.12204668 ◽

2020 ◽

Author(s):

Ancy Iruthayaraj ◽

Sivanandam Magudeeswaran ◽

Kumaradhas Poomani

Keyword(s):

Clinical Trial ◽

Amino Acids ◽

Free Energy ◽

Binding Free Energy ◽

Drug Repurposing ◽

Md Simulations ◽

Binding Mechanism ◽

Main Protease ◽

Repurposed Drugs ◽

Hiv 1

Initially, the SARS-CoV-2 virus was emerged from Wuhan, China and rapidly spreading across the world and urges the scientific community to develop antiviral therapeutic agents. Among several strategies, drug repurposing will help to react immediately to overcome COVID-19 pandemic. In the present study, we have chosen two clinical trial drugs TMB607 and TMC310911 are the inhibitors of HIV-1 protease to use as the inhibitors of SARS-CoV-2 main protease (Mpro) enzyme. To make use of these two inhibitors as the repurposed drugs for COVID-19, it is essential to know the molecular basis of binding mechanism of these two molecules with the SARS-CoV-2 main protease (Mpro). Understand the binding mechanism; we performed the molecular docking, molecular dynamics (MD) simulations and binding free energy calculations against the SARS-CoV-2 Mpro. The docking results indicate that both molecules form intermolecular interactions with the active site amino acids of Mpro enzyme. However, during the MD simulations, TMB607 forms strong interactions with the key amino acids of Mpro and remains intact. The RMSD and RMSF values of both complexes were stable throughout the MD simulations. The MM-GBSA binding free energy values of both complexes are -43.7 and -34.9 kcal/mol, respectively. This in silico study proves that the TMB607 molecule binds strongly with the SARS-CoV-2 Mpro enzyme and it is suitable for the drug repurposing of COVID-19 and further drug designing.

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Insights to the Binding of a Selective Adenosine A3 Receptor Antagonist using Molecular Dynamics Simulations, Binding Free Energy Calculations and Mutagenesis

10.26434/chemrxiv.9248918.v1 ◽

2019 ◽

Author(s):

Panagiotis Lagarias ◽

Kerry Barkan ◽

Eva Tzortzini ◽

Eleni Vrontaki ◽

Margarita Stampelou ◽

...

Keyword(s):

Free Energy ◽

Computational Model ◽

Molecular Mechanics ◽

Surface Area ◽

Binding Free Energy ◽

Md Simulations ◽

Free Energy Calculations ◽

Binding Energies ◽

Energy Calculations ◽

Binding Free Energy Calculations

Adenosine A3 receptor (A3R), is a promising drug target against cancer cell proliferation. Currently there is no experimentally determined structure of A3R. Here, we have investigate a computational model, previously applied successfully for agonists binding to A3R, using molecular dynamic (MD) simulations, Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations. Extensive computations were performed to explore the binding profile of O4-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbonyl}-2-methyl-1,3-thiazole-4-carbohydroximamide (K18) to A3R. K18 is a new specific and competitive antagonist at the orthosteric binding site of A3R, discovered using virtual screening and characterized pharmacologically in our previous studies. The most plausible binding conformation for the dichlorophenyl group of K18 inside the A3R is oriented towards trans-membrane helices (TM) 5 and 6, according to the MM-PBSA and MM-GBSA binding free energy calculations, and by the previous results obtained by mutating residues of TM5, TM6 to alanine which reduce antagonist potency. The results from 14 site-directed mutagenesis experiments were interpreted using MD simulations and MM-GBSA calculations which show that the relative binding free energies of the mutant A3R - K18 complexes compare to the WT A3R are in agreement with the effect of the mutations, i.e. the reduction, maintenance or increase of antagonist potency. We show that when the residues V1695.30, M1775.38, I2496.54 involved in direct interactions with K18 are mutated to alanine, the mutant A3R - K18 complexes reduce potency, increase the RMSD value of K18 inside the binding area and the MM-GBSA binding free energy compared to the WT A3R complex. Our computational model shows that other mutant A3R complexes with K18, including directly interacting residues, i.e. F1685.29A, L2466.51A, N2506.55A complexes with K18 are not stable. In these complexes of A3R mutated in directly interacting residues one or more of the interactions between K18 and these residues are lost. In agreement with the experiments, the computations show that, M1745.35 a residue which does not make direct interactions with K18 is critical for K18 binding. A striking results is that the mutation of residue V1695.30 to glutamic acid maintained antagonistic potency. This effect is in agreement with the binding free energy calculations and it is suggested that is due to K18 re-orientation but also to the plasticity of A3R binding area. The mutation of direct interacting L903.32 in the low region and the non-directly interacting L2647.35 to alanine in the middle region increases the antagonistic potency, suggesting that chemical modifications of K18 can be applied to augment antagonistic potency. The calculated binding energies ΔGeff values of K18 against mutant A3Rs displayed very good correlation with experimental potencies (pA2 values). These results further approve the computational model for the description of K18 binding with critical residues of the orthosteric binding area which can have implications for the design of more effective antagonists based on the structure of K18.

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Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria

BioMed Research International ◽

10.1155/2017/5270940 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 7

Author(s):

Shailima Rampogu ◽

Ayoung Baek ◽

Minky Son ◽

Amir Zeb ◽

Chanin Park ◽

...

Keyword(s):

Binding Free Energy ◽

Genetic Disorder ◽

Md Simulations ◽

Free Energy Calculations ◽

Premature Aging ◽

Farnesyltransferase Inhibitors ◽

Docking Simulations ◽

Lipinski’S Rule ◽

Computational Exploration ◽

The Stability

Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski’s rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.

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Effectiveness of Natural Antioxidants against SARS-CoV-2? Insights from the In-Silico World

Antibiotics ◽

10.3390/antibiotics10081011 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1011

Author(s):

Muhammad Fayyaz ur Rehman ◽

Shahzaib Akhter ◽

Aima Iram Batool ◽

Zeliha Selamoglu ◽

Mustafa Sevindik ◽

...

Keyword(s):

Molecular Docking ◽

Protein Interactions ◽

Dissociation Constants ◽

Antiviral Agents ◽

Natural Antioxidants ◽

Md Simulations ◽

Binding Energies ◽

Protein Targets ◽

Docking Simulations ◽

Main Protease

The SARS CoV-2 pandemic has affected millions of people around the globe. Despite many efforts to find some effective medicines against SARS CoV-2, no established therapeutics are available yet. The use of phytochemicals as antiviral agents provides hope against the proliferation of SARS-CoV-2. Several natural compounds were analyzed by virtual screening against six SARS CoV-2 protein targets using molecular docking simulations in the present study. More than a hundred plant-derived secondary metabolites have been docked, including alkaloids, flavonoids, coumarins, and steroids. SARS CoV-2 protein targets include Main protease (MPro), Papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), Spike glycoprotein (S), Helicase (Nsp13), and E-Channel protein. Phytochemicals were evaluated by molecular docking, and MD simulations were performed using the YASARA structure using a modified genetic algorithm and AMBER03 force field. Binding energies and dissociation constants allowed the identification of potentially active compounds. Ligand-protein interactions provide an insight into the mechanism and potential of identified compounds. Glycyrrhizin and its metabolite 18-β-glycyrrhetinic acid have shown a strong binding affinity for MPro, helicase, RdRp, spike, and E-channel proteins, while a flavonoid Baicalin also strongly binds against PLpro and RdRp. The use of identified phytochemicals may help to speed up the drug development and provide natural protection against SARS-CoV-2.

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Insights to the Binding of a Selective Adenosine A3 Receptor Antagonist using Molecular Dynamics Simulations, Binding Free Energy Calculations and Mutagenesis

10.26434/chemrxiv.9248918 ◽

2019 ◽

Author(s):

Panagiotis Lagarias ◽

Kerry Barkan ◽

Eva Tzortzini ◽

Eleni Vrontaki ◽

Margarita Stampelou ◽

...

Keyword(s):

Free Energy ◽

Computational Model ◽

Molecular Mechanics ◽

Surface Area ◽

Binding Free Energy ◽

Md Simulations ◽

Free Energy Calculations ◽

Binding Energies ◽

Energy Calculations ◽

Binding Free Energy Calculations

Adenosine A3 receptor (A3R), is a promising drug target against cancer cell proliferation. Currently there is no experimentally determined structure of A3R. Here, we have investigate a computational model, previously applied successfully for agonists binding to A3R, using molecular dynamic (MD) simulations, Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations. Extensive computations were performed to explore the binding profile of O4-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbonyl}-2-methyl-1,3-thiazole-4-carbohydroximamide (K18) to A3R. K18 is a new specific and competitive antagonist at the orthosteric binding site of A3R, discovered using virtual screening and characterized pharmacologically in our previous studies. The most plausible binding conformation for the dichlorophenyl group of K18 inside the A3R is oriented towards trans-membrane helices (TM) 5 and 6, according to the MM-PBSA and MM-GBSA binding free energy calculations, and by the previous results obtained by mutating residues of TM5, TM6 to alanine which reduce antagonist potency. The results from 14 site-directed mutagenesis experiments were interpreted using MD simulations and MM-GBSA calculations which show that the relative binding free energies of the mutant A3R - K18 complexes compare to the WT A3R are in agreement with the effect of the mutations, i.e. the reduction, maintenance or increase of antagonist potency. We show that when the residues V1695.30, M1775.38, I2496.54 involved in direct interactions with K18 are mutated to alanine, the mutant A3R - K18 complexes reduce potency, increase the RMSD value of K18 inside the binding area and the MM-GBSA binding free energy compared to the WT A3R complex. Our computational model shows that other mutant A3R complexes with K18, including directly interacting residues, i.e. F1685.29A, L2466.51A, N2506.55A complexes with K18 are not stable. In these complexes of A3R mutated in directly interacting residues one or more of the interactions between K18 and these residues are lost. In agreement with the experiments, the computations show that, M1745.35 a residue which does not make direct interactions with K18 is critical for K18 binding. A striking results is that the mutation of residue V1695.30 to glutamic acid maintained antagonistic potency. This effect is in agreement with the binding free energy calculations and it is suggested that is due to K18 re-orientation but also to the plasticity of A3R binding area. The mutation of direct interacting L903.32 in the low region and the non-directly interacting L2647.35 to alanine in the middle region increases the antagonistic potency, suggesting that chemical modifications of K18 can be applied to augment antagonistic potency. The calculated binding energies ΔGeff values of K18 against mutant A3Rs displayed very good correlation with experimental potencies (pA2 values). These results further approve the computational model for the description of K18 binding with critical residues of the orthosteric binding area which can have implications for the design of more effective antagonists based on the structure of K18.

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Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

10.26434/chemrxiv.12442736.v1 ◽

2020 ◽

Author(s):

Serdar Durdagi

Keyword(s):

Clinical Investigation ◽

Binding Free Energy ◽

Drug Repurposing ◽

Md Simulations ◽

Positive Control ◽

New Drugs ◽

In Vivo Studies ◽

Approved Drugs

Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.

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Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

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Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578.v1 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

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