Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses.

Alexander J Craig,Yoseph Atilaw,Ylva Gravenfors,Laura Vangeel,Ali Taş ,Bo Lundgren,Janina Krambrich,Hjalmar Gullberg,Jens Carlsson,Steven De Jonghe,Johan Neyts,U Helena Danielson,Martijn J Van Hemert,Andreas Luttens,Anna Sandström ,Åke Lundkvist,Lindon W K Moodie,Johan Lennerstrand,Duy Duc Vo,Kristian Sandberg,Dirk Jochmans,V Talibov ,Dario Akaberi,Eldar Abdurakhmanov,Natalia Nekhotiaeva,Jan Kihlberg

doi:10.1021/jacs.1c08402

Abstract

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.

Highlights

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the greatest health crisis of this generation and already led to >5 million deaths worldwide.[1]
In the first virtual screen, 235 million compounds were docked to a crystal structure of main protease (Mpro) determined in complex with the substrate-based inhibitor X77 (PDB code: 6W6325)
Three main findings emerged from our virtual screens of ultralarge chemical libraries for SARS-CoV-2 inhibitors

Summary

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the greatest health crisis of this generation and already led to >5 million deaths worldwide.[1]. Variants of SARS-CoV-2 for which the vaccines are less effective have already emerged, which is a strong indication that antiviral drugs are needed to complement vaccines in the long term.[2] Analogous to common cold viruses, SARS-CoV-2 is expected to continue to circulate and remain a major threat to our society. In this scenario, antiviral agents are needed to treat patients that have been infected as well as be given prophylactically to protect high-risk groups. The noncovalent scaffolds were peptidomimetics, a chemotype that tends to have poor pharmacokinetic properties, and covalent modifiers typically require extensive optimization to modulate activity and selectivity.[10−12] It was clear that development of safe and efficacious drugs targeting coronavi-

Methods

Results

Conclusion