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  • Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning
Title: Unveiling the molecular mechanism of SARS-CoV-2 main protease inhibition from 137 crystal structures using algebraic topology and deep learning
Currently, there is neither effective antiviral drugs nor vaccine for coronavirus disease 2019 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to its high conservativeness and low similarity with human genes, SARS-CoV-2 main protease (M pro ) is one of the most favorable drug targets. However, the current understanding of the molecular mechanism of M pro inhibition is limited by the lack of reliable binding affinity ranking and prediction of existing structures of M pro –inhibitor complexes. This work integrates mathematics ( i.e. , algebraic topology) and deep learning (MathDL) to provide a reliable ranking of the binding affinities of 137 SARS-CoV-2 M pro inhibitor structures. We reveal that Gly143 residue in M pro is the most attractive site to form hydrogen bonds, followed by Glu166, Cys145, and His163. We also identify 71 targeted covalent bonding inhibitors. MathDL was validated on the PDBbind v2016 core set benchmark and a carefully curated SARS-CoV-2 inhibitor dataset to ensure the reliability of the present binding affinity prediction. The present binding affinity ranking, interaction analysis, and fragment decomposition offer a foundation for future drug discovery efforts.  more » « less
Award ID(s):
1761320 1900473
PAR ID:
10272158
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Chemical Science
Volume:
11
Issue:
44
ISSN:
2041-6520
Page Range / eLocation ID:
12036 to 12046
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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