Structure-based drug design of an inhibitor of the SARS-CoV-2 (COVID-19) main protease using free software: A tutorial for students and scientists

Eur J Med Chem. 2021 Jun 5;218:113390. doi: 10.1016/j.ejmech.2021.113390. Epub 2021 Mar 20.


This paper describes the structure-based design of a preliminary drug candidate against COVID-19 using free software and publicly available X-ray crystallographic structures. The goal of this tutorial is to disseminate skills in structure-based drug design and to allow others to unleash their own creativity to design new drugs to fight the current pandemic. The tutorial begins with the X-ray crystallographic structure of the main protease (Mpro) of the SARS coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera software to modify the substrate to create a cyclic peptide inhibitor within the Mpro active site. Finally, the tutorial uses the molecular docking software AutoDock Vina to show the interaction of the cyclic peptide inhibitor with both SARS-CoV Mpro and the highly homologous SARS-CoV-2 Mpro. The supporting information provides an illustrated step-by-step protocol, as well as a video showing the inhibitor design process, to help readers design their own drug candidates for COVID-19 and the coronaviruses that will cause future pandemics. An accompanying preprint in bioRxiv [] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.

Keywords: AutoDock vina; Main protease (M(pro)) inhibitor; Molecular modeling tutorial; SARS-CoV-2; Structure-based drug design (SBDD); UCSF Chimera.

MeSH terms

  • Antiviral Agents / chemistry*
  • Binding Sites
  • COVID-19 / drug therapy
  • Catalytic Domain
  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / chemistry
  • Drug Design*
  • Drug Discovery*
  • Humans
  • Protease Inhibitors / chemistry*
  • Protein Binding
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / enzymology*
  • Software


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