An Updated Review of Computer-Aided Drug Design and Its Application to COVID-19

Abstract

The recent outbreak of the deadly coronavirus disease 19 (COVID-19) pandemic poses serious health concerns around the world. The lack of approved drugs or vaccines continues to be a challenge and further necessitates the discovery of new therapeutic molecules. Computer-aided drug design has helped to expedite the drug discovery and development process by minimizing the cost and time. In this review article, we highlight two important categories of computer-aided drug design (CADD), viz., the ligand-based as well as structured-based drug discovery. Various molecular modeling techniques involved in structure-based drug design are molecular docking and molecular dynamic simulation, whereas ligand-based drug design includes pharmacophore modeling, quantitative structure-activity relationship (QSARs), and artificial intelligence (AI). We have briefly discussed the significance of computer-aided drug design in the context of COVID-19 and how the researchers continue to rely on these computational techniques in the rapid identification of promising drug candidate molecules against various drug targets implicated in the pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The structural elucidation of pharmacological drug targets and the discovery of preclinical drug candidate molecules have accelerated both structure-based as well as ligand-based drug design. This review article will help the clinicians and researchers to exploit the immense potential of computer-aided drug design in designing and identification of drug molecules and thereby helping in the management of fatal disease.

Figure 1

Basic steps involved in the structure-based drug design approach.

Figure 2

Molecules currently investigated in clinical trials where molecules 1-5 in the orange box are RNA polymerase inhibitors, molecules 6-8 in the yellow box are 3C-like protease inhibitors, molecule 9 in the green box is a papain-like protease inhibitor, molecules 10-13 in the blue box are TMPRSS2 inhibitors, and molecules 14-15 in the grey box are inhibitors of endosomal acidification.

Figure 3

The structural proteins of SARS-CoV-2.

Figure 4

Macromolecular target structures of SARS-CoV-2. (a) X-ray crystal structure of the SARS-CoV-2 main protease in complex with an inhibitor N3 (PDB ID: 7BQY). (b) Crystal structure of Nsp12 (RdRp) bound to triphosphate form of remdesivir (PDB ID: 7BV2). (c) Crystal structure of the SARS-CoV-2 papain-like protease in complex with peptide inhibitor VIR250 (PDB ID: 6WUU). (d) Crystal structure of Nsp15 endoribonuclease from SARS-CoV-2 in complex with potential repurposing drug tipiracil (PDB ID: 6WXC). (e) Crystal structure of the SARS-CoV-2 helicase (PDB ID: 6ZSL). (f) Crystal structure of Nsp16 (2′-O-methyltransferase) from SARS-CoV-2 in complex with sinefungin. The secondary structure elements—helices, sheets, and loops—are colored in red, cyan, and grey, respectively, and the bound inhibitors are rendered as a ball-and-stick model.