Molecular Dynamics Simulations Indicate the COVID-19 Mpro Is Not a Viable Target for Small-Molecule Inhibitors Design

Maria Bzówka, Karolina Mitusińska, Agata Raczyńska, Aleksandra Samol, Jack Tuszyński, Artur Góra

10.1101/2020.02.27.968008

Research curated

Abstract

The coronavirus outbreak took place in December 2019 and continues to spread worldwide. In the absence of an effective vaccine, inhibitor repurposing may seem a fruitful attempt. Here, we compared Mpros from SARS-CoV-2 and SARS-CoV. Despite a high level of sequence similarity, the binding sites of analysed proteins show major differences in both shape and size indicating that repurposing SARS drugs for COVID-19 may be futile. Furthermore, the analysis of the pockets conformational changes during the simulation time indicates their flexibility, which dashes hopes for rapid and reliable drug design. Conversely, structural stability of the SARS-CoV-2 Mpro with respect to mutations of the binding cavity and adjacent flexible loops indicates that the proteins mutability will pose a further challenge to the rational design of small-molecule inhibitors. However, few residues contribute significantly to the protein stability and thus can be considered as key anchoring residues for Mpro inhibitor design.

Source: BioRxiv

Related molecules

Name	Synonyms	Genes
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b