Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro

  • Sci Rep. 2024 Apr 14;14(1):8620. doi: 10.1038/s41598-024-59292-0.
Kaio Maciel de Santiago-Silva  1 ,  Priscila Goes Camargo  1 ,  Larissa Esteves Carvalho Constant  2 ,  Stephany da Silva Costa  2 ,  Giovanna Barbosa Frensel  2 ,  Diego Allonso  2 ,  Gerson Nakazato  3 ,  Camilo Henrique da Silva Lima  4 ,  Marcelle de Lima Ferreira Bispo  5
Affiliations
  • 1. Laboratório de Síntese de Moléculas Medicinais (LaSMMed), Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Londrina, Brazil.
  • 2. Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, RJ, 21941-902, Brazil.
  • 3. Departamento de Microbiologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil.
  • 4. Departamento de Química Orgânica, Instituto de Química, Universidade Federal Do Rio de Janeiro, Rio de Janeiro, Brazil.
  • 5. Laboratório de Síntese de Moléculas Medicinais (LaSMMed), Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Londrina, Brazil. [email protected].
PMID: 38616188 DOI: 10.1038/s41598-024-59292-0
Abstract

Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC50 value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively.

Keywords
3CL protease; COVID-19; Coronavirus; Inhibitors; Molecular docking; Molecular dynamics.
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