Inhibitors of the SARS-CoV-2 Papain-like Protease
Del Mundo, Zachary P., 1999--
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The papain-like protease (PLpro) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a target enzyme for treatment of the 2019 coronavirus infectious disease (COVID-19). Multiple lead competitive inhibitors to the protease have been previously discovered, particularly VIR250, HGN1034, and GYX402. Analogs of these ligands were designed using ChemSketch or Chem3D. The ligand-active site interactions of those unique ligands were observed and compared using AutoDock Tools, which also computes a predicted inhibitory constant (Ki) . Over the Fall 2020 semester, proficiency in performing several functions of AutoDock Tools was acquired, and a total of thirteen unique and original compounds designed based on the aforementioned leads were tested. Three analogs of HGN1034 showed to have the strongest potential for future research and application: ZDM16 had the closest docking pose to the lead HGN1034 (Ki ZDM16 = 329.04 nM); ZDM13 and ZDM14 had the lowest computed inhibitory constants, lower than that of HGN1034 (Ki ZDM14 = 15.96 nM < Ki ZDM13 = 16.45 nM < Ki HGN1034 = 19.78 nM). The limitations of computational chemistry are considered and rationalized, and prospective follow-up studies and possibilities for future designs of inhibitors of the SARS-CoV-2 PLpro enzyme are discussed.