Ensemble-based virtual screening of African natural products to target human thymidylate synthase.
J Mol Graph Model
; 125: 108568, 2023 12.
Article
em En
| MEDLINE
| ID: mdl-37591123
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Timidilato Sintase
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article