Application of molecular dynamics-based pharmacophore and machine learning approaches to identify novel Mcl1 inhibitors through drug repurposing and mechanics research.
Phys Chem Chem Phys
; 26(22): 16107-16124, 2024 Jun 06.
Article
en En
| MEDLINE
| ID: mdl-38780456
ABSTRACT
Myeloid cell leukemia 1 (Mcl1), a critical protein that regulates apoptosis, has been considered as a promising target for antitumor drugs. The conventional pharmacophore screening approach has limitations in conformation sampling and data mining. Here, we offered an innovative solution to identify Mcl1 inhibitors with molecular dynamics-refined pharmacophore and machine learning methods. Considering the safety and druggability of FDA-approved drugs, virtual screening of the database was performed to discover Mcl1 inhibitors, and the hit was subsequently validated via TR-FRET, cytotoxicity, and flow cytometry assays. To reveal the binding characteristics shared by the hit and a typical Mcl1 selective inhibitor, we employed quantum mechanics and molecular mechanics (QM/MM) calculations, umbrella sampling, and metadynamics in this work. The combined studies suggested that fluvastatin had promising cell inhibitory potency and was suitable for further investigation. We believe that this research will shed light on the discovery of novel Mcl1 inhibitors that can be used as a supplemental treatment against leukemia and provide a possible method to improve the accuracy of drug repurposing with limited computational resources while balancing the costs of experimentation well.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Simulación de Dinámica Molecular
/
Reposicionamiento de Medicamentos
/
Proteína 1 de la Secuencia de Leucemia de Células Mieloides
/
Aprendizaje Automático
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
PCCP. Phys. chem. chem. phys. (Print)
/
PCCP. Physical chemistry chemical physics (Print)
/
Phys Chem Chem Phys
Asunto de la revista:
BIOFISICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article