20.500.12556/DKUM-86901 Identification of triazolopyrimidinyl scaffold SARS-CoV-2 papain-like protease (PLpro) 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 papainlike protease (PLpro), 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 PLpro, 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 PLpro, and we stress its potential for further optimization. Moreover, besides compound 372 as a candidate for PLpro inhibitor development, this study elaborates on the PLpro binding site dynamics and provides a valuable contribution for further efforts in pan-coronaviral PLpro inhibitor development. drug design protease inhibitor SARS-CoV-2 papain-like protease PLpro antiviral design in silico drug design CADD virtual screening HTVS structure-based design zdravila inhibitorji proteaze proteaza true false true MDPI Angleški jezik Slovenski jezik https://www.mdpi.com/journal/pharmaceutics © 2024 by the authors Članek v reviji 2024-01-26 10:38:17 2024-01-26 10:38:17 2025-07-01 12:44:28 0000-00-00 00:00:00 2024 0 0 13 str. iss. 2, [article no.] 169 Vol. 16 25 Jan. 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2023-12-11 2024-01-22 2024-01-25 60:543.2/.9 182627331 10.3390/pharmaceutics16020169 1999-4923 pharmaceutics-16-00169.pdf pharmaceutics-16-00169.pdf 1 589EA9EE19F6AA2E9E2CDBD80BC06BD2 cf714cc8cd93ca33dd5b2d56576a750514e64a1373ee862ba7875601301e0f46 d57ab969-bc2f-11ee-9e06-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=175676 https://www.mdpi.com/1999-4923/16/2/169 0 abc9d3aa-5666-11f0-8520-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=193033 Fakulteta za kemijo in kemijsko tehnologijo 0 0 0