1. Co-crystallization and structure determination: An effective direction for anti-SARS-CoV-2 drug discovery
- Author
-
Xian-En Zhao, Liyan Yang, and Zhonglei Wang
- Subjects
IC50, half maximal inhibitory concentration ,Review ,Biochemistry ,SI, selectivity index ,Structural Biology ,cryo-EM, cryo-electron microscopy ,media_common ,COVID-19, coronavirus disease 2019 ,MMPBSA, molecular mechanics Poisson-Boltzmann surface area ,MTase, methyltransferase ,Natural products ,PLpro, papain-like protease ,Drug discovery ,Chemistry ,DyKAT, dynamic kinetic asymmetric transformation ,MERS-CoV, Middle East respiratory syndrome coronavirus ,SAM, S-adenosylmethionine ,Ligand (biochemistry) ,MD, molecular dynamics ,Computer Science Applications ,EC50, half maximal effective concentration ,EBOV, Ebola virus ,HCoV-229E, human coronavirus 229E ,Biotechnology ,Drug ,2019-20 coronavirus outbreak ,3CLpro, 3C-Like protease ,FDA-approved drugs ,Coronavirus disease 2019 (COVID-19) ,media_common.quotation_subject ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Highly pathogenic ,SARS-CoV, severe acute respiratory syndrome coronavirus ,Biophysics ,Ugi-4CR, Ugi four-component reaction ,Computational biology ,ACE2, angiotensin-converting enzyme 2 ,SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 ,EMD, Electron Microscopy Data ,PDB, Protein Data Bank ,Co-crystal structures ,Genetics ,RdRp, RNA-dependent RNA polymerase ,Nsp, nonstructural protein ,ComputingMethodologies_COMPUTERGRAPHICS ,Candidate drugs ,RTP, ribonucleoside triphosphate ,SARS-CoV-2 ,FDA, U.S. Food and Drug Administration ,Mpro, main protease ,HPLC, high-performance liquid chromatography ,TP248.13-248.65 - Abstract
Graphical 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 (PLpro, Mpro, 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.
- Published
- 2021