20.500.12556/RUL-164981 Identification of triazolopyrimidinyl scaffold SARS-CoV-2 papain-like protease (PL$^{pro}$) inhibitor The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its companion disease, COVID-19, has reminded us of the importance of basic coronaviral research. In this study, a comprehensive approach using molecular docking, in vitro assays, and molecular dynamics simulations was applied to identify potential inhibitors for SARS-CoV-2 papain-like protease (PL$^{pro}$), a key and underexplored viral enzyme target. A focused protease inhibitor library was initially created and molecular docking was performed using CmDock software (v0.2.0), resulting in the selection of hit compounds for in vitro testing on the isolated enzyme. Among them, compound 372 exhibited promising inhibitory properties against PL$^{pro}$, with an IC50 value of 82 ± 34 µM. The compound also displayed a new triazolopyrimidinyl scaffold not yet represented within protease inhibitors. Molecular dynamics simulations demonstrated the favorable binding properties of compound 372. Structural analysis highlighted its key interactions with PL$^{pro}$, and we stress its potential for further optimization. Moreover, besides compound 372 as a candidate for PL$^{pro}$ inhibitor development, this study elaborates on the PL$^{pro}$ binding site dynamics and provides a valuable contribution for further efforts in pan-coronaviral PL$^{pro}$ inhibitor development. drug design protease inhibitor SARS-CoV-2 papain-like protease PL$^{pro}$ antiviral design in silico drug design CADD virtual screening HTVS structure-based design zdravila inhibitorji proteaze proteaza true false true Angleški jezik Slovenski jezik Članek v reviji 2024-11-19 14:36:05 2024-11-19 14:36:06 2024-11-20 03:53:55 0000-00-00 00:00:00 2024 0 0 13 str. iss. 2, art. 169 Vol. 16 Feb. 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 60:543.2/.9 1999-4923 10.3390/pharmaceutics16020169 182627331 pharmaceutics-16-00169.pdf pharmaceutics-16-00169.pdf 1 4A9C292DD0FC8DF46942F6DBEDEEA609 c20a3745811e693ff59e74b6df0ddd33a53c33844a6cf9b77ddf54aa73f9f9cd 7f6981c2-a67b-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=195877 https://www.mdpi.com/1999-4923/16/2/169 0 1c9bd7c3-a67b-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=195876 Biotehniška fakulteta 0 0 0