Kaempferol as a Potential PAK4 Inhibitor in Triple Negative Breast Cancer: Extra Precision Glide Docking and Free Energy Calculation

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 poses 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.

Potential Molecular Mechanisms of Chaihu‐Shugan‐San in Treatment of Breast Cancer Based on Network Pharmacology

“…Beta-sitosterol can promote the apoptosis of breast cancer cells by activating the Fas signaling pathway and caspase-8 activity [ 32 ] and is expected to be an orphan nutrition drug against cancer [ 33 ]. Kaempferol has shown a good affinity for PAK4 in molecular docking and is considered to be a potential inhibitor in triple-negative breast cancer [ 34 ], and kaempferol can prevent G2/M phase of the cell cycle by downregulating CDK1 in human breast cancer MDA-MB-453 cells [ 35 ], and blocking RhoA and Rac1 signaling pathways to inhibit breast cancer cell migration and invasion [ 36 ] is a powerful antioxidant inducer and can inhibit oncogene transformation and induce cancer cell apoptosis and DNA damage. Quercetin, naringenin, and isorhamnetin, such as flavonoids, can prevent breast cancer cell migration through inflammatory and apoptotic cell signaling [ 37 , 38 ], and quercetin can induce autophagy by inhibiting the Akt-mTOR pathway [ 39 ].…”

Sanyin Formula Enhances the Therapeutic Efficacy of Paclitaxel in Triple-Negative Breast Cancer Metastases through the JAK/STAT3 Pathway in Mice

“…Previous studies showed that these potential active components exhibit antitumor effects. Kaempferol inhibits breast cancer cell proliferation, induces apoptosis, and suppresses cell migration by regulating the AKT, MEK, and PKC/MAPK pathways [ 14 , 15 , 16 , 17 ]. p-Coumaric acid induces cancer cell apoptosis by regulating nuclear damage and repair and apoptosis-related gene expression in MDA-MB-231 cells [ 18 ].…”

Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents

“…In addition, many natural products have also been reported as potential PAK4 inhibitors, including vitexin, emodin, ziganein, and kaempferol ( Arowosegbe et al, 2020 ; Iwaloye et al, 2021 ). However, these compounds generally possess much modest potency against PAK4, and the underlying mechanism needs to be further validated as well.…”