Fragment Molecular Orbital Based Interaction Analyses on COVID-19 Main Protease − Inhibitor N3 Complex (PDB ID: 6LU7)

Hatada, Ryo; Okuwaki, Koji; Mochizuki, Yuji; Handa, Yuma; Fukuzawa, Kaori; Komeiji, Yuto; Okiyama, Yoshio; Tanaka, Shigenori

doi:10.1021/acs.jcim.0c00283

Cited by 93 publications

(97 citation statements)

References 41 publications

(93 reference statements)

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“…S3b). These two viral proteases also share similar folding and crystal structures (14,15). In this study, we found that GC376 is an extremely potent inhibitor of the M pro encoded by SARS-CoV-2, with a half-maximum inhibitory concentration (IC 50 ) of 26.4 Ϯ 1.1 nM (Fig.…”

Section: Resultsmentioning

confidence: 64%

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Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

Hung

Huang

et al. 2020

Antimicrob Agents Chemother

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The COVID-19 pandemic caused by SARS-CoV-2 is a health threat worldwide. Viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a therapeutic target for drug discovery. Herein, we report that GC376, a broad-spectrum inhibitor targeting Mpro in the picornavirus-like supercluster, is potent inhibitor for the Mpro encoded by SARS-CoV-2 with half-maximum inhibitory concentration (IC50) of 26.4±1.1 nM. In this study, we also show that GC376 inhibits SARS-CoV-2 replication with a half-maximum effective concentration (EC50) of 0.91±0.03 μM. Only a small portion of SARS-CoV-2-Mpro was covalently modified in the excess of GC376 as evaluated by mass spectrometry analysis; indicating that improved inhibitors are needed. Subsequently, molecular docking analysis revealing the recognition and binding groups of GC376 within the active site of SARS-CoV-2 Mpro provides important new information for the optimization of GC376. Given that sufficient safety and efficacy data are available for GC376 as an investigational veterinary drug, expedited development of GC376, or its optimized analogues, for treatment of SARS-CoV-2 infection in human is recommended.

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Section: Resultsmentioning

confidence: 64%

“…The docking of compounds to the binding sites of SARS-CoV-2 M pro (NCBI Protein Data Bank accession no. 6LU7) (14) or M pro of feline infectious peritonitis virus, FIPV M pro (NCBI Protein Data Bank accession no. 4ZRO) (6), was explored using the BIOVIA 2018/LigandFit program (BIOVIA, Inc., San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

Hung

Huang

et al. 2020

Antimicrob Agents Chemother

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“…The crystal structure of monomeric SARS-COV-2 Mpro was obtained from the Protein Data Bank with the identity of 6Y2F. 11 It should be noted that the computational investigations of promising inhibitors for SARS-CoV-2 Mpro are possible for the monomeric form 25,26 because the SARS-CoV-2 Mpro dimer interface does not contain the substrate-binding cle. 11,12 Ligand structures were taken from the ZINC15 in man only and the PubChem database.…”

Section: Structure Of Ligands and Sars-cov-2 Mpromentioning

confidence: 99%

Rapid prediction of possible inhibitors for SARS-CoV-2 main protease using docking and FPL simulations

Pham

et al. 2020

RSC Adv.

103

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“…The main protease has also been a target for many different structure-based studies, including the design of covalent inhibitors guided by X-ray crystallography (PDB IS: 6LZE and 6M0K) [ 159 ] and the description of pharmacophore through MD simulations involving His41, Gly143 and Glu166 [ 160 ]. Another in-depth description of the molecular interactions between the SARS-CoV-2 3CLpro and its peptide-like inhibitor N3 using FMO (please see section Structural bioinformatics tools and resources to support therapeutics discovery) suggests guidelines for chemical optimization in situ [ 161 ]. Furthermore, Altay et al.…”

Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

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SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

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Fragment Molecular Orbital Based Interaction Analyses on COVID-19 Main Protease − Inhibitor N3 Complex (PDB ID: 6LU7)

Cited by 93 publications

References 41 publications

Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

Discovery of M Protease Inhibitors Encoded by SARS-CoV-2

Rapid prediction of possible inhibitors for SARS-CoV-2 main protease using docking and FPL simulations

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

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