In silico hit optimization toward AKT inhibition: fragment-based approach, molecular docking and molecular dynamics study.
J Biomol Struct Dyn
; 37(16): 4301-4311, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-30477412
ABSTRACT
Protein kinase B also known as AKT is a cardinal node in different signaling pathways that regulates diverse cell processes. AKT has three isoforms that share high homology. Hyperactivation of each isoform is related with different types of cancer. This work describes the computational search for new inhibitors using a hit optimization process of the previously reported AKT pan inhibitor, a 2,4,6-trisubstituted pyridine. A database of new molecules was proposed using a variant of fragment-based docking methodology and previous reported considerations. Molecular docking followed by molecular dynamics studies were performed to select the best compounds and analyze their behavior. Protein-ligand complexes energy was calculated using molecular mechanics Poisson-Boltzmann surface area protocol. Further, proposed molecules were compared with the ChEMBL database of compounds assayed against AKT. Data analysis leads to determine the structural requirements necessary for a favorable interaction of the proposed ligands with the AKT pocket. Molecular dynamics data suggested that the pKa of the ligands is important for the stability in the AKT pocket. Molecular similarity analysis shows that proposed ligands have not been previously reported. Thus, ligands with high docking scores and favorable behavior on molecular dynamics simulations are proposed as potential AKT inhibitors.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ligação Proteica
/
Termodinâmica
/
Inibidores de Proteínas Quinases
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Proteínas Proto-Oncogênicas c-akt
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Biomol Struct Dyn
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
México