Chemical space exploration with Molpher: Generating and assessing a glucocorticoid receptor ligand library

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22310%2F24%3A43931127" target="_blank" >RIV/60461373:22310/24:43931127 - isvavai.cz</a>

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/epdf/10.1002/minf.202300316" target="_blank" >https://onlinelibrary.wiley.com/doi/epdf/10.1002/minf.202300316</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/minf.202300316" target="_blank" >10.1002/minf.202300316</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Chemical space exploration with Molpher: Generating and assessing a glucocorticoid receptor ligand library

Popis výsledku v původním jazyce

Computational exploration of chemical space is crucial in modern cheminformatics research for accelerating the discovery of new biologically active compounds. In this study, we present a detailed analysis of the chemical library of potential glucocorticoid receptor (GR) ligands generated by the molecular generator, Molpher. To generate the targeted GR library and construct the classification models, structures from the ChEMBL database as well as from the internal IMG library, which was experimentally screened for biological activity in the primary luciferase reporter cell assay, were utilized. The composition of the targeted GR ligand library was compared with a reference library that randomly samples chemical space. A random forest model was used to determine the biological activity of ligands, incorporating its applicability domain using conformal prediction. It was demonstrated that the GR library is significantly enriched with GR ligands compared to the random library. Furthermore, a prospective analysis demonstrated that Molpher successfully designed compounds, which were subsequently experimentally confirmed to be active on the GR. A collection of 34 potential new GR ligands was also identified. Moreover, an important contribution of this study is the establishment of a comprehensive workflow for evaluating computationally generated ligands, particularly those with potential activity against targets that are challenging to dock. © 2024 The Authors. Molecular Informatics published by Wiley-VCH GmbH.

Název v anglickém jazyce

Chemical space exploration with Molpher: Generating and assessing a glucocorticoid receptor ligand library

Popis výsledku anglicky

Computational exploration of chemical space is crucial in modern cheminformatics research for accelerating the discovery of new biologically active compounds. In this study, we present a detailed analysis of the chemical library of potential glucocorticoid receptor (GR) ligands generated by the molecular generator, Molpher. To generate the targeted GR library and construct the classification models, structures from the ChEMBL database as well as from the internal IMG library, which was experimentally screened for biological activity in the primary luciferase reporter cell assay, were utilized. The composition of the targeted GR ligand library was compared with a reference library that randomly samples chemical space. A random forest model was used to determine the biological activity of ligands, incorporating its applicability domain using conformal prediction. It was demonstrated that the GR library is significantly enriched with GR ligands compared to the random library. Furthermore, a prospective analysis demonstrated that Molpher successfully designed compounds, which were subsequently experimentally confirmed to be active on the GR. A collection of 34 potential new GR ligands was also identified. Moreover, an important contribution of this study is the establishment of a comprehensive workflow for evaluating computationally generated ligands, particularly those with potential activity against targets that are challenging to dock. © 2024 The Authors. Molecular Informatics published by Wiley-VCH GmbH.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10602 - Biology (theoretical, mathematical, thermal, cryobiology, biological rhythm), Evolutionary biology

Projekt

<a href="/cs/project/LM2023052" target="_blank" >LM2023052: Národní infrastruktura chemické biologie</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

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

Název periodika

Molecular Informatics

ISSN

1868-1743

e-ISSN

—

Svazek periodika

43

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

TW - Čínská republika (Tchaj-wan)

Počet stran výsledku

24

Strana od-do

—

Kód UT WoS článku

001268141400001

EID výsledku v databázi Scopus

2-s2.0-85197786625