Ensemble-based virtual screening of African natural products to target human thymidylate synthase.
African natural products
Cancer therapies
Ensemble docking
Human thymidylate synthase
Relaxed complex scheme
Virtual screening
Journal
Journal of molecular graphics & modelling
ISSN: 1873-4243
Titre abrégé: J Mol Graph Model
Pays: United States
ID NLM: 9716237
Informations de publication
Date de publication:
12 2023
12 2023
Historique:
received:
19
04
2023
revised:
11
07
2023
accepted:
12
07
2023
medline:
25
9
2023
pubmed:
18
8
2023
entrez:
17
8
2023
Statut:
ppublish
Résumé
Human thymidylate synthase (hTS) is a validated drug target for chemotherapy. A virtual screening experiment was used to prioritize a list of compounds from African Natural Products Databases docked against the orthosteric binding pocket of hTS. Consensus scores of binding affinities from ensemble-based virtual screening, hydrated docking and MM-PBSA calculations ranked compounds NEA4433 and NEA4434 as the best candidates owing to binding affinity scores in the picomolar order, their excellent ADMET profiles and the good stability of the protein-ligand complexes formed. The current study demonstrates the role of water in small molecule binding to hTS in mediating protein-ligand interactions. Similarly, the robust ensemble docking (relaxed scheme complex) ranked NEA4433 and NEA4434 as the best candidates. Furthermore, the best candidates prioritized were shown to strongly interact with the same residues that interacted with hTS substrate and cofactor.
Identifiants
pubmed: 37591123
pii: S1093-3263(23)00166-3
doi: 10.1016/j.jmgm.2023.108568
pii:
doi:
Substances chimiques
Thymidylate Synthase
EC 2.1.1.45
Ligands
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108568Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Denis Mteremko reports financial support was provided by The World Bank, through The Africa Centre for Research, Agricultural Advancement, Teaching Excellence and Sustainability (CREATES).