Protein-ligand binding affinity prediction of cyclin-dependent kinase-2 inhibitors by dynamically averaged fragment molecular orbital-based interaction energy.
J Comput Chem
; 43(20): 1362-1371, 2022 07 30.
Article
en En
| MEDLINE
| ID: mdl-35678372
ABSTRACT
Fragment molecular orbital (FMO) method is a powerful computational tool for structure-based drug design, in which protein-ligand interactions can be described by the inter-fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO-based approach in which molecular dynamics simulations were used to generate multiple protein-ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA-IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X-ray crystal structures was R2 = 0.75. Using the DA-IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of -1 was added, the DA FMO-based scheme with the dispersion energies still achieved R2 = 0.99, whereas R2 decreased to 0.32 employing all the energy terms of PIEDA.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas
/
Simulación de Dinámica Molecular
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Año:
2022
Tipo del documento:
Article