Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation.

Autor: Sousa BKP; Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Goiás 74690-900, Brazil., Mottin M; Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Goiás 74690-900, Brazil.; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil., Seanego D; Holistic Drug Discovery and Development Centre (H3D), University of Cape Town, Cape Town 7701, South Africa., Jurisch CD; Holistic Drug Discovery and Development Centre (H3D), University of Cape Town, Cape Town 7701, South Africa., Rodrigues BSA; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil., da Silva VLS; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil., Andrade MA; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil., Morais GS; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil., Boerin DF; Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.; Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil., Froes TQ; Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.; Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil., Motta FN; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil.; Faculdade de Ceilândia, Universidade de Brasília, Brasília, Distrito Federal 73345-010, Brazil., Nonato MC; Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.; Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil., Bastos IDM; Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 73345-010, Brazil., Chibale K; Holistic Drug Discovery and Development Centre (H3D), University of Cape Town, Cape Town 7701, South Africa.; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Cape Town 7701, South Africa.; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7701, South Africa., Gessner RK; Holistic Drug Discovery and Development Centre (H3D), University of Cape Town, Cape Town 7701, South Africa., Andrade CH; Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.; Laboratory for Molecular Modeling and Drug Design (LabMol), Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Goiás 74690-900, Brazil.; Center for Excellence in Artificial Intelligence (CEIA), Instituto de Informática, Universidade Federal de Goiás, Goiânia, Goiás 74690-900, Brazil.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Dec 02; Vol. 15 (12), pp. 2140-2149. Date of Electronic Publication: 2024 Dec 02 (Print Publication: 2024).
DOI: 10.1021/acsmedchemlett.4c00420
Abstrakt: The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC 50 of 73.61 μM and a K i of 22 μM. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC 50 values between 15.06 and 51.81 μM. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro.
Competing Interests: The authors declare no competing financial interest.
(© 2024 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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