Identification of repurposing therapeutics toward SARS-CoV-2 main protease by virtual screening

PLoS One. 2022 Jun 30;17(6):e0269563. doi: 10.1371/journal.pone.0269563. eCollection 2022.

Abstract

SARS-CoV-2 causes the current global pandemic coronavirus disease 2019. Widely-available effective drugs could be a critical factor in halting the pandemic. The main protease (3CLpro) plays a vital role in viral replication; therefore, it is of great interest to find inhibitors for this enzyme. We applied the combination of virtual screening based on molecular docking derived from the crystal structure of the peptidomimetic inhibitors (N3, 13b, and 11a), and experimental verification revealed FDA-approved drugs that could inhibit the 3CLpro of SARS-CoV-2. Three drugs were selected using the binding energy criteria and subsequently performed the 3CLpro inhibition by enzyme-based assay. In addition, six common drugs were also chosen to study the 3CLpro inhibition. Among these compounds, lapatinib showed high efficiency of 3CLpro inhibition (IC50 value of 35 ± 1 μM and Ki of 23 ± 1 μM). The binding behavior of lapatinib against 3CLpro was elucidated by molecular dynamics simulations. This drug could well bind with 3CLpro residues in the five subsites S1', S1, S2, S3, and S4. Moreover, lapatinib's key chemical pharmacophore features toward SAR-CoV-2 3CLpro shared important HBD and HBA with potent peptidomimetic inhibitors. The rational design of lapatinib was subsequently carried out using the obtained results. Our discovery provides an effective repurposed drug and its newly designed analogs to inhibit SARS-CoV-2 3CLpro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / metabolism
  • Drug Repositioning
  • Humans
  • Lapatinib / pharmacology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Peptidomimetics* / pharmacology
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Peptidomimetics
  • Protease Inhibitors
  • Lapatinib
  • 3C-like proteinase, SARS-CoV-2
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases

Grants and funding

This research is funded by Thailand Science Research and Innovation Fund Chulalongkorn University (CU) (CU_FRB65_hea(71)_134_23_64) (Fundamental Fund 2565, CU). K.S. and Pa.W. are supported by the Second Century Fund (C2F),Chulalongkorn University. KW is partially supported by the Institute for the Promotion of Teaching Science and Technology(IPST) under the Research Fund for DPST Graduate with First Placement [Grant no. 08/2559], the CU grant to the Center of Excellence for Molecular Biology and Genomics of Shrimp, and the Molecular Crop Research Unit. P.D. is partially supported by the 90th Anniversary of the CU Scholarship and the Science Achievement Scholarship of Thailand (SAST). TR is partially supported by the National Council of Thailand (NRCT), grant number N42A650231.