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

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 (M pro ) 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 M pro 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 M pro and the highly homologous SARS-CoV-2 M pro . 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 [

A Multidisciplinary Approach to Coronavirus Disease (COVID-19)

“…The drug design process has useful multi-step tools to avoid time-consuming and expensive investigation [113]. This process has two different approaches: Structure-based or ligand-based computer-aided drug design [114][115][116][117][118][119]. Both methods are suitable for SARS-CoV-2 and lots of results have been obtained for use in clinical treatment.…”

Structure-based design and synthesis of copper(ii) complexes as antivirus drug candidates targeting SARS CoV-2 and HIV

“…5 SARS-CoV-2 causes infected cells to express a main protease (M pro or 3CL protease) that is responsible for site-specifically cleaving the polyprotein, which is translated from viral m-RNA within human cells. 6 The proteolytic activity of M pro is essential to the virus to generate the individual proteins that are necessary for replication and infection. The essential role of M pro , as well as the success of HIV protease inhibitors in the treatment of HIV/AIDS, makes M pro an attractive therapeutic target to treat SARS-CoV-2.…”

High predictive QSAR models for predicting the SARS coronavirus main protease inhibition activity of ketone-based covalent inhibitors

“…Generally, designed drugs for COVID-19 treatment can be classified into four groups including drugs that prevent the replication and synthesis of RNA by targeting critical enzymes for the replication of the virus, drugs that block the binding of spike protein to ACE2 receptor on human cells, drugs that inhibit coronavirus virulence factors and drugs that inhibit a receptor or enzymes in human cells [ 24 ]. 3C-like cysteine protease (3CL pro ) is the main protease of SARS-CoV-2 that catalyzes the cleavage of polypeptides to their effector forms and has essential enzymatic role for virus life cycle [ 25 , 26 ]. So it can be considered as a target for design drugs in COVID-19 treatment [ 27 – 29 ].…”