Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation.
J Chem Inf Model
; 63(9): 2828-2841, 2023 05 08.
Article
en En
| MEDLINE
| ID: mdl-37060320
ABSTRACT
Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Adenilil Ciclasas
/
Descubrimiento de Drogas
Idioma:
En
Revista:
J Chem Inf Model
Asunto de la revista:
INFORMATICA MEDICA
/
QUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos