Kaempferol as a Potential PAK4 Inhibitor in Triple Negative Breast Cancer: Extra Precision Glide Docking and Free Energy Calculation.
Curr Drug Discov Technol
; 17(5): 682-695, 2020.
Article
em En
| MEDLINE
| ID: mdl-31441728
ABSTRACT
BACKGROUND:
P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many human tumors, particularly in Triple Negative Breast Cancer (TNBC) progression. Studies have revealed the crucial role of PAK4 in cell proliferation, anchorage-independent growth and cell migration among other hallmarks of cancer. Thus, PAK4 is an attractive target for anti-TNBC drug design and development. In our research, we used in silico methods to investigate the inhibitory potentials of kaempferol against PAK4 as compared with co-crystallized 4T6 and a standard PAK4 inhibitor-KPT-9274. The ligands were docked into the ATP-binding site of the target enzyme and post-docking validations were calculated.RESULTS:
In the molecular docking results, kaempferol had higher affinity than the standard KPT-9274. However, the SP and XP docking scores for the co-crystallized 4T6 were the highest. The analyses of the docking showed a favorable interaction between kaempferol and the catalytic-important aminoacyl residues, especially GLU396, LEU398 and ASP458 in the ATP-binding site of PAK4 when compared with what was obtained in the 4T6-PAK4 complex. Molecular mechanics based MM-GBSA was used to validate docking results. The free energy calculations revealed that kaempferol may have a favorable biological activity. Furthermore, the druggability of each ligand was assessed using the QikProp module and the SwissADME online tool. Kaempferol possessed a propitious drug-like property when compared to the standard ligands.CONCLUSIONS:
We, therefore, put forward a logical argument that kaempferol can be further evaluated as a potential PAK4 inhibitor in TNBC.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quempferóis
/
Inibidores de Proteínas Quinases
/
Quinases Ativadas por p21
/
Neoplasias de Mama Triplo Negativas
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article