Open AccessUltralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses
Author(s) -
Andreas Luttens,
Hjalmar Gullberg,
Eldar Abdurakhmanov,
Duy Duc Vo,
Dario Akaberi,
V. Talibov,
Natalia Nekhotiaeva,
Laura Vangeel,
Steven De Jonghe,
Dirk Jochmans,
Janina Krambrich,
Ali Taş,
Bo Lundgren,
Ylva Gravenfors,
Alexander J. Craig,
Yoseph Atilaw,
Anna Sandström,
Lindon W. K. Moodie,
Åke Lundkvist,
Martijn J. van Hemert,
Johan Neyts,
Johan Lennerstrand,
Jan Kihlberg,
Kristian Sandberg,
U. Helena Danielson,
Jens Carlsson
Publication year - 2022
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c08402
Subject(s) - virtual screening , docking (animal) , chemistry , coronavirus , protease , covid-19 , active site , small molecule , computational biology , broad spectrum , enzyme , in vitro , binding site , virology , drug discovery , combinatorial chemistry , biochemistry , outbreak , biology , infectious disease (medical specialty) , medicine , nursing , disease , pathology
Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.