2. Academic Validation
  3. Inhibitor induced conformational changes in SARS-COV-2 papain-like protease

Inhibitor induced conformational changes in SARS-COV-2 papain-like protease

  • Sci Rep. 2022 Jul 8;12(1):11585. doi: 10.1038/s41598-022-15181-y.
Glaucio Monteiro Ferreira 1,  Thanigaimalai Pillaiyar 2,  Mario Hiroyuki Hirata 1,  Antti Poso 3 4,  Thales Kronenberger 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Av Prof Lineu Prestes 580, São Paulo, 05508-000, Brazil.
  • 2 Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
  • 3 Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany.
  • 4 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
  • 5 Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany. kronenberger7@gmail.com.
  • 6 Department of Oncology and Pneumonology, Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany. kronenberger7@gmail.com.
  • 7 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland. kronenberger7@gmail.com.
  • 8 Tübingen Center for Academic Drug Discovery and Development (TüCAD2), 72076, Tübingen, Germany. kronenberger7@gmail.com.
PMID: 35803957 DOI: 10.1038/s41598-022-15181-y
Abstract

SARS-CoV-2's papain-like protease (PLpro) interaction with ligands has recently been explored with a myriad of crystal structures. We used molecular dynamics (MD) simulations to study different PLpro-ligand complexes, their ligand-induced conformational changes, and interactions. We focused on inhibitors reported with known IC50 against PLpro, namely GRL-0617, XR8-89, PLP_Snyder530, and Sander's recently published compound 7 (CPD7), and compared these trajectories against the apostructure (Apo), with a total of around 60 µs worth simulation data. We aimed to study the conformational changes using molecular dynamics simulations for the inhibitors in the PLpro. PCA analyses and the MSM models revealed distinct conformations of PLpro in the absence/presence of ligands and proposed that BL2-loop contributes to the accessibility of these inhibitors. Further, bulkier substituents closer to Tyr268 and Gln269 could improve inhibition of SARS-CoV-2 PLpro by occupying the region between BL2-groove and BL2-loop, but we also expand on the relevance of exploring multiple PLpro sub-pockets to improve inhibition.

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