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Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F22%3A00557969" target="_blank" >RIV/86652036:_____/22:00557969 - isvavai.cz</a>

  • Výsledek na webu

    <a href="https://www.mdpi.com/2075-1729/12/5/659" target="_blank" >https://www.mdpi.com/2075-1729/12/5/659</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.3390/life12050659" target="_blank" >10.3390/life12050659</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy

  • Popis výsledku v původním jazyce

    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.

  • Název v anglickém jazyce

    Computational Investigations on the Natural Small Molecule as an Inhibitor of Programmed Death Ligand 1 for Cancer Immunotherapy

  • Popis výsledku anglicky

    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.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10608 - Biochemistry and molecular biology

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/NU21-03-00372" target="_blank" >NU21-03-00372: Malé vazebné proteiny cílené na proteiny imunitní kontrolní dráhy PD-1/PD-L1 jako nové diagnostické nástroje</a><br>

  • Návaznosti

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2022

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Life

  • ISSN

    2075-1729

  • e-ISSN

    2075-1729

  • Svazek periodika

    12

  • Číslo periodika v rámci svazku

    5

  • Stát vydavatele periodika

    CH - Švýcarská konfederace

  • Počet stran výsledku

    22

  • Strana od-do

    659

  • Kód UT WoS článku

    000801896000001

  • EID výsledku v databázi Scopus

    2-s2.0-85129939980