Co-crystallization and structure determination: An effective direction for anti-SARS-CoV-2 drug discovery

Abstract

Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PL^pro, M^pro, RdRp, and S glycoprotein) offers a valuable direction for anti-SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.

Keywords: 3CLpro, 3C-Like protease; ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; Candidate drugs; Co-crystal structures; DyKAT, dynamic kinetic asymmetric transformation; EBOV, Ebola virus; EC50, half maximal effective concentration; EMD, Electron Microscopy Data; FDA, U.S. Food and Drug Administration; FDA-approved drugs; HCoV-229E, human coronavirus 229E; HPLC, high-performance liquid chromatography; IC50, half maximal inhibitory concentration; MD, molecular dynamics; MERS-CoV, Middle East respiratory syndrome coronavirus; MMPBSA, molecular mechanics Poisson-Boltzmann surface area; MTase, methyltransferase; Mpro, main protease; Natural products; Nsp, nonstructural protein; PDB, Protein Data Bank; PLpro, papain-like protease; RTP, ribonucleoside triphosphate; RdRp, RNA-dependent RNA polymerase; SAM, S-adenosylmethionine; SARS-CoV, severe acute respiratory syndrome coronavirus; SARS-CoV-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SI, selectivity index; Ugi-4CR, Ugi four-component reaction; cryo-EM, cryo-electron microscopy.