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
Conclusions: We, therefore, put forward a logical argument that kaempferol can be further evaluated as a
potential PAK4 inhibitor in TNBC.