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

S Zhang, M Krumberger, MA Morris… - European journal of …, 2021 - Elsevier
European journal of medicinal chemistry, 2021Elsevier
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 (M pro) of the SARS
coronavirus (SARS-CoV) bound to a peptide substrate and then uses the UCSF Chimera …
Abstract
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 [https://doi.org/10.1101/2020.08.03.234872] describes the synthesis of the cyclic peptide and the experimental validation as an inhibitor of SARS-CoV-2 Mpro.
Elsevier
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