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Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease.
J Biomol Struct Dyn. 2020 Jun 01 [Online ahead of print]JB

Abstract

The recent pandemic of severe acute respiratory syndrome-coronavirus2 (SARS-CoV-2) infection (COVID-19) has put the world on serious alert. The main protease of SARS-CoV-2 (SARS-CoV-2-MPro) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the SARS-CoV-2-MPro binding site. A huge library of 191678 fragments was screened against the binding cavity of SARS-CoV-2-MPro and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET filters and MM-GBSA binding energy calculations to select 17 best molecules (named as MP-In1 to MP-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with SARS-CoV-2-MPro, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with SARS-CoV-2-MPro. Fifteen molecules were found to form stable complexes with SARS-CoV-2-MPro. These novel chemical entities designed specifically according to the pharmacophoric requirements of SARS-CoV-2-MPro binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for SARS-CoV-2 drug discovery. [Formula: see text]Communicated by Ramaswamy H. Sarma.

Authors+Show Affiliations

Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32452282

Citation

Choudhury, Chinmayee. "Fragment Tailoring Strategy to Design Novel Chemical Entities as Potential Binders of Novel Corona Virus Main Protease." Journal of Biomolecular Structure & Dynamics, 2020, pp. 1-14.
Choudhury C. Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease. J Biomol Struct Dyn. 2020.
Choudhury, C. (2020). Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease. Journal of Biomolecular Structure & Dynamics, 1-14. https://doi.org/10.1080/07391102.2020.1771424
Choudhury C. Fragment Tailoring Strategy to Design Novel Chemical Entities as Potential Binders of Novel Corona Virus Main Protease. J Biomol Struct Dyn. 2020 Jun 1;1-14. PubMed PMID: 32452282.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fragment tailoring strategy to design novel chemical entities as potential binders of novel corona virus main protease. A1 - Choudhury,Chinmayee, Y1 - 2020/06/01/ PY - 2020/5/27/pubmed PY - 2020/5/27/medline PY - 2020/5/27/entrez KW - Covid-19 KW - docking KW - fragment-based drug discovery KW - main protease KW - molecular dynamics SP - 1 EP - 14 JF - Journal of biomolecular structure & dynamics JO - J. Biomol. Struct. Dyn. N2 - The recent pandemic of severe acute respiratory syndrome-coronavirus2 (SARS-CoV-2) infection (COVID-19) has put the world on serious alert. The main protease of SARS-CoV-2 (SARS-CoV-2-MPro) cleaves the long polyprotein chains to release functional proteins required for replication of the virus and thus is a potential drug target to design new chemical entities in order to inhibit the viral replication in human cells. The current study employs state of art computational methods to design novel molecules by linking molecular fragments which specifically bind to different constituent sub-pockets of the SARS-CoV-2-MPro binding site. A huge library of 191678 fragments was screened against the binding cavity of SARS-CoV-2-MPro and high affinity fragments binding to adjacent sub-pockets were tailored to generate new molecules. These newly formed molecules were further subjected to molecular docking, ADMET filters and MM-GBSA binding energy calculations to select 17 best molecules (named as MP-In1 to MP-In17), which showed comparable binding affinities and interactions with the key binding site residues as the reference ligand. The complexes of these 17 molecules and the reference molecule with SARS-CoV-2-MPro, were subjected to molecular dynamics simulations, which assessed the stabilities of their binding with SARS-CoV-2-MPro. Fifteen molecules were found to form stable complexes with SARS-CoV-2-MPro. These novel chemical entities designed specifically according to the pharmacophoric requirements of SARS-CoV-2-MPro binding pockets showed good synthetic feasibility and returned no exact match when searched against chemical databases. Considering their interactions, binding efficiencies and novel chemotypes, they can be further evaluated as potential starting points for SARS-CoV-2 drug discovery. [Formula: see text]Communicated by Ramaswamy H. Sarma. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/32452282/Fragment_tailoring_strategy_to_design_novel_chemical_entities_as_potential_binders_of_novel_corona_virus_main_protease_ L2 - http://www.tandfonline.com/doi/full/10.1080/07391102.2020.1771424 DB - PRIME DP - Unbound Medicine ER -
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