Molecular mechanisms of inhibitor bindings to A-FABP deciphered by using molecular dynamics simulations and calculations of MM-GBSA.
SAR QSAR Environ Res
; 32(4): 293-315, 2021 Apr.
Article
em En
| MEDLINE
| ID: mdl-33655818
ABSTRACT
Adipocyte fatty-acid binding protein (A-FABP) plays a central role in many aspects of metabolic diseases. It is an important target in drug design for treatment of FABP-related diseases. In this study, molecular dynamics (MD) simulations followed by calculations of molecular mechanics generalized Born surface area (MM-GBSA) and principal components analysis (PCA) were implemented to decipher molecular mechanism correlating with binding of inhibitors 57Q, 57P and L96 to A-FABP. The results show that van der Waals interactions are the leading factors to control associations of 57Q, 57P, and L96 with A-FABP, which reveals an energetic basis for designing of clinically available inhibitors towards A-FABP. The information from PCA and cross-correlation analysis rationally unveils that inhibitor bindings affect conformational changes of A-FABP and change relative movements between residues. Decomposition of binding affinity into contributions of individual residues not only detects hot spots of inhibitor/A-FABP binding but also shows that polar interactions of the positively charged residue Arg126 with three inhibitors provide a significant contribution for stabilization of the inhibitor/A-FABP bindings. Furthermore, the binding strength of L96 to residues Ser55, Phe57 and Lys58 are stronger than that of inhibitors 57Q and 57P to these residues.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação a Ácido Graxo
/
Simulação de Dinâmica Molecular
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
SAR QSAR Environ Res
Assunto da revista:
SAUDE AMBIENTAL
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China