Fragment-based in silico design of SARS-CoV-2 main protease inhibitors

Document Type

Article

Publication Date

10-1-2021

Publication Title

Chemical Biology and Drug Design

Volume

98

Issue

4

First Page

604

Keywords

coronavirus COVID-19, fragment-based drug discovery, main protease Mpro 3CLpro, multivalency, SARS-CoV-2, X-ray crystal structure

Last Page

619

Abstract

3CLpro is essential for SARS-CoV-2 replication and infection; its inhibition using small molecules is a potential therapeutic strategy. In this study, a comprehensive crystallography-guided fragment-based drug discovery approach was employed to design new inhibitors for SARS-CoV-2 3CLpro. All small molecules co-crystallized with SARS-CoV-2 3CLpro with structures deposited in the Protein Data Bank were used as inputs. Fragments sitting in the binding pocket (87) were grouped into eight geographical types. They were interactively coupled using various synthetically reasonable linkers to generate larger molecules with divalent binding modes taking advantage of two different fragments' interactions. In total, 1,251 compounds were proposed, and 7,158 stereoisomers were screened using Glide (standard precision and extra precision), AutoDock Vina, and Prime MMGBSA. The top 22 hits having conformations approaching the linear combination of their constituent fragments were selected for MD simulation on Desmond. MD simulation suggested 15 of these did adopt conformations very close to their constituent pieces with far higher binding affinity than either constituent domain alone. These structures could provide a starting point for the further design of SARS-CoV-2 3CLpro inhibitors with improved binding, and structures are provided.

DOI

10.1111/cbdd.13914

ISSN

17470277

E-ISSN

17470285

PubMed ID

34148292

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