scholarly journals Identification of potential COVID-19 main protease inhibitors using structure-based pharmacophore approach, molecular docking and repurposing studies

2021 ◽  
Vol 71 (2) ◽  
pp. 163-174
Author(s):  
Safa Daoud ◽  
Shada J. Alabed ◽  
Lina A. Dahabiyeh
Keyword(s):  
Binding Site ◽  
Protease Inhibitors ◽  
Specific Binding ◽  
Antiviral Drug ◽  
Pharmacophore Model ◽  
Docking Study ◽  
Pharmacophore Modeling ◽  
Antiviral Drugs ◽  
Crystallographic Structure ◽  
Main Protease

AbstractThe current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today’s diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.

scholarly journals Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7385
Author(s):  
Wei Yu ◽  
Xiaomin Wu ◽  
Yizhen Zhao ◽  
Chun Chen ◽  
Zhiwei Yang ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Computational Simulation ◽  
Antiviral Drug ◽  
Interaction Mechanism ◽  
Pharmacophore Model ◽  
Md Simulations ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Hydrogen Bond Donor ◽  
Main Protease

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM–GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.

scholarly journals Theoretical Evaluation of Bortezomib and Other Boron-Containing Compounds as Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Ivan Ricardo Vega Valdez ◽  
Jose-Martin Santiago-Quintana ◽  
MELVIN ROSALEZ ◽  
Eunice Farfan ◽  
Marvin A. Soriano-Ursua
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Boron Atom ◽  
Docking Study ◽  
Theoretical Evaluation ◽  
Main Protease ◽  
Potent Inhibition ◽  
Drug Designing ◽  
Key Residues

The aim of the present docking study was to explore the putative role of boronic moieties in molecules interacting on the binding site of the SARS-CoV-2 main protease. The methodology was based on the conventional docking procedure by means of AutoDock software by assaying boron-free and boron-containing compounds on the recent reported crystal structure of SARS-CoV-2 main protease (PDB code: 6LU7). The most of tested compounds share contact with key residues and poses on the cleavage pocket. Those compounds with a boron atom in its structure often were estimated with higher affinity than boron-free analogues. Interactions and affinity of boron-containing peptidomimetics on the binding site let us to propose the potent inhibition of these compounds on targeted protease. These advances may be relevant for drug designing, but also to suggest the testing of available boron-containing drugs in patients with severe symptoms of COVID19 infection.

scholarly journals Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

2020 ◽  
Author(s):  
pooja singh ◽  
Angkita Sharma ◽  
Shoma Paul Nandi
Keyword(s):  
Molecular Docking ◽  
Antiviral Drug ◽  
Cyclopiazonic Acid ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Docking Score ◽  
Protease Enzyme ◽  
Main Protease

<p>Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease M<sup>pro</sup>, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in <i>Aspergillus flavus</i> and <i>Aspergillus oryzae</i> fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth <i>in- vitro</i> and <i>in-vivo</i>.<b> </b></p>

scholarly journals Investigation of interaction between close and open types of SARS-Cov-2 spike glycoprotein with synthesized and natural Compounds as inhibitor; Molecular Docking Study

2020 ◽  
Author(s):  
Masume Jomhori ◽  
Hamid Mosaddeghi
Keyword(s):  
Binding Site ◽  
Receptor Binding ◽  
Antiviral Drug ◽  
Severe Infection ◽  
Docking Study ◽  
Spike Protein ◽  
Spike Glycoprotein ◽  
Molecular Docking Study ◽  
Antiviral Compound ◽  
Pubchem Database

Abstract Purpose Viral diseases are increasingly endangering universal public health because of a shortage of successful antiviral therapies. The novel pandemic 2019 n-Cov2 disease (COVID-19) is recently identified as viral disorder triggered by a new type of coronavirus. This type of coronavirus binds to the host human receptors through the Spike glycoprotein(S) Receptor Binding Domain (RBD). Two types of spike protein have been identified in open and closed states in which the open type causes severe infection. Thus, this receptor is a significant target for antiviral drug design.Methods Totally 111*2 natural and synthetic compounds were chosen from the PubChem database as ligands. To recognize the ability of direct contact between ligands and the binding site of 2019 n-Cov 2 -ACE2 protein, we have docked all compounds to the protein using AutoDock Vina. The FaF3-Drugs, Pan Assay Intrusion Compounds (PAINS), absorption, distribution, metabolism, excretion (ADME) and Lipinski's rules were used to evaluate the drug-like properties of the identified ligands. Antiviral compound prediction (AVC pred) also was used to assess antivirus properties.Results The results showed that seven ligands out of all had interactions with spike protein-angiotensin converting enzyme 2 binding site. We have found that six out of seven ligands show drug-like characteristics. We also found that the fluorophenyl and propane groups of ligands had the best interaction with the binding site of the protein.Conclusion Further, our results showed the ability of these ligands to prevent receptor binding of the spike protein SARS-CoV-2, so they would be considered as novel compounds of COVID-19 therapy drugs.

scholarly journals Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning

2020 ◽  
Vol 11 (44) ◽  
pp. 12036-12046
Author(s):  
Duc Duy Nguyen ◽  
Kaifu Gao ◽  
Jiahui Chen ◽  
Rui Wang ◽  
Guo-Wei Wei
Keyword(s):  
Deep Learning ◽  
Binding Site ◽  
Crystal Structures ◽  
Protease Inhibitors ◽  
Molecular Mechanism ◽  
Algebraic Topology ◽  
Binding Affinities ◽  
Protease Inhibition ◽  
Site Analysis ◽  
Main Protease

By integrating algebraic topology and deep learning, we provide a reliable ranking of binding affinities, binding site analysis, and fragment decomposition for 137 SARS-CoV-2 main protease inhibitors.

An expedited approach towards the rationale design of non-covalent SARS-CoV-2 main protease inhibitors with in vitro antiviral activity

2020 ◽  
Author(s):  
Naoya Kitamura ◽  
Michael Dominic Sacco ◽  
Chunlong Ma ◽  
Yanmei Hu ◽  
Julia Alma Townsend ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Binding Site ◽  
Antiviral Drug ◽  
Binding Pocket ◽  
Native Mass Spectrometry ◽  
Calpain Inhibitor ◽  
Site Analysis ◽  
Main Protease ◽  
Covalent Inhibitors

AbstractThe main protease (Mpro) of SARS-CoV-2 is a validated antiviral drug target. Several Mpro inhibitors have been reported with potent enzymatic inhibition and cellular antiviral activity, including GC376, boceprevir, calpain inhibitors II and XII, each containing a reactive warhead that covalently modifies the catalytic Cys145. In this study, we report an expedited drug discovery approach by coupling structure-based design and Ugi four-component (Ugi-4CR) reaction methodology to the design of non-covalent Mpro inhibitors. The most potent compound 23R had cellular antiviral activity similar to covalent inhibitors such as GC376. Our designs were guided by overlaying the structure of SARS-CoV Mpro + ML188 (R), a non-covalent inhibitor derived from Ug-4CR, with the X-ray crystal structures of SARS-CoV-2 Mpro + calpain inhibitor XII/GC376/UAWJ247. Binding site analysis suggests a strategy of extending the P2 and P3 substitutions in ML188 (R) to achieve optimal shape complementary with SARS-CoV-2 Mpro. Lead optimization led to the discovery of 23R, which inhibits SARS-CoV-2 Mpro and SARS-CoV-2 viral replication with an IC50 of 0.31 μM and EC50 of 1.27 μM, respectively. The binding and specificity of 23R to SARS-CoV-2 Mpro were confirmed in a thermal shift assay and native mass spectrometry assay. The co-crystal structure of SARS-CoV-2 Mpro with 23R revealed the P2 biphenyl fits snuggly into the S2 pocket and the benzyl group in the α-methylbenzyl faces towards the core of the enzyme, occupying a previously unexplored binding site located in between the S2 and S4 pockets. Overall, this study revealed the most potent non-covalent SARS-CoV-2 Mpro inhibitors reported to date and a novel binding pocket that can be explored for Mpro inhibitor design.

scholarly journals Antiviral Drug Discovery To Address the COVID-19 Pandemic

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Douglas D. Richman
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Discovery ◽  
Antiviral Drug ◽  
Antiviral Drugs ◽  
Morbidity And Mortality ◽  
Main Protease ◽  
Lead Inhibitors ◽  
Global Population

ABSTRACT The magnitude of the morbidity and mortality inflicted upon the global population in less than 1 year has driven the inescapable conclusion that the discovery and development of effective antiviral drugs for COVID-19 are urgent and should be prioritized. The antiviral drug discovery programs that emerged for HIV and hepatitis C virus have enabled technology and expertise to accelerate this process for SARS-CoV-2. The description of candidate lead inhibitors for the viral main protease (Mpro) exemplifies this accelerated approach and reminds us of the needs and opportunities for addressing this pandemic.

scholarly journals Theoretical Evaluation of Bortezomib and Other Boron-Containing Compounds as Inhibitors of SARS-CoV-2 Main Protease

2020 ◽  
Author(s):  
Ivan Ricardo Vega Valdez ◽  
Jose-Martin Santiago-Quintana ◽  
MELVIN ROSALEZ ◽  
Eunice Farfan ◽  
Marvin A. Soriano-Ursua
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Boron Atom ◽  
Docking Study ◽  
Theoretical Evaluation ◽  
Main Protease ◽  
Potent Inhibition ◽  
Drug Designing ◽  
Key Residues

The aim of the present docking study was to explore the putative role of boronic moieties in molecules interacting on the binding site of the SARS-CoV-2 main protease. The methodology was based on the conventional docking procedure by means of AutoDock software by assaying boron-free and boron-containing compounds on the recent reported crystal structure of SARS-CoV-2 main protease (PDB code: 6LU7). The most of tested compounds share contact with key residues and poses on the cleavage pocket. Those compounds with a boron atom in its structure often were estimated with higher affinity than boron-free analogues. Interactions and affinity of boron-containing peptidomimetics on the binding site let us to propose the potent inhibition of these compounds on targeted protease. These advances may be relevant for drug designing, but also to suggest the testing of available boron-containing drugs in patients with severe symptoms of COVID19 infection.

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