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Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy
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SYSNO ASEP 0557969 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy Author(s) Kumar, G. (IN)
Moustafa, M. (SA)
Sahoo, A. (IN)
Malý, Petr (BTO-N) RID, ORCID
Bharadwaj, Shiv (BTO-N)Number of authors 5 Article number 659 Source Title Life. - : MDPI
Roč. 12, č. 5 (2022)Number of pages 22 s. Language eng - English Country CH - Switzerland Keywords BINDING FREE-ENERGIES ; MM-PBSA ; PROTEIN ; DOCKING Subject RIV EB - Genetics ; Molecular Biology OECD category Biochemistry and molecular biology R&D Projects NU21-03-00372 GA MZd - Ministry of Health (MZ) Method of publishing Open access Institutional support BTO-N - RVO:86652036 UT WOS 000801896000001 EID SCOPUS 85129939980 DOI 10.3390/life12050659 Annotation Several therapeutic monoclonal antibodies approved by the FDA are available against the PD-1/PD-L1 (programmed death 1/programmed death ligand 1) immune checkpoint axis, which has been an unprecedented success in cancer treatment. However, existing therapeutics against PD-L1, including small molecule inhibitors, have certain drawbacks such as high cost and drug resistance that challenge the currently available anti-PD-L1 therapy. Therefore, this study presents the screening of 32,552 compounds from the Natural Product Atlas database against PD-L1, including three steps of structure-based virtual screening followed by binding free energy to refine the ideal conformation of potent PD-L1 inhibitors. Subsequently, five natural compounds, i.e., Neoenactin B1, Actinofuranone I, Cosmosporin, Ganocapenoid A, and 3-[3-hydroxy-4-(3-methylbut-2-enyl)phenyl]-5-(4-hydroxybenzyl)-4-methyldihydrofuran-2(3H)-one, were collected based on the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling and binding free energy (>-60 kcal/mol) for further computational investigation in comparison to co-crystallized ligand, i.e., JQT inhibitor. Based on interaction mapping, explicit 100 ns molecular dynamics simulation, and end-point binding free energy calculations, the selected natural compounds were marked for substantial stability with PD-L1 via intermolecular interactions (hydrogen and hydrophobic) with essential residues in comparison to the JQT inhibitor. Collectively, the calculated results advocate the selected natural compounds as the putative potent inhibitors of PD-L1 and, therefore, can be considered for further development of PD-L1 immune checkpoint inhibitors in cancer immunotherapy. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2023 Electronic address https://www.mdpi.com/2075-1729/12/5/659
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