Halogen Bonding Hot Spots as a Constraint in Virtual Screening: A Case Study of 5-HT7R.
J Med Chem
; 67(16): 14007-14015, 2024 Aug 22.
Article
em En
| MEDLINE
| ID: mdl-39082690
ABSTRACT
The recently developed and used molecular modeling approach to search for privileged amino acids for halogen bonding (XB hot spots) through XSAR sets has been applied to 5-HT7R. Herein, among all identified 5-HT7R XB hot spots, the S5x42 was employed in a virtual screening protocol as a constraint. Through a designed virtual screening protocol, 63 XSAR sets (156 compounds) were selected from more than 8 million commercially available compounds and examined using in vitro assay toward 5-HT7R. A 68% accuracy was found in predicting halogenated derivatives with higher affinity for 5-HT7R than their unsubstituted analogs. Moreover, it was observed that a halogen bond formed between S5x42 and a chlorine atom at the 3-position of the arylpiperazine fragment caused the most remarkable, 35.4-fold increase in binding affinity for 5-HT7R when compared to the nonhalogenated analog. Interestingly, molecular dynamics simulations showed the formation of a bifurcated halogen bond with S5x42.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptores de Serotonina
/
Halogênios
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article