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

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

Volume: 17 Issue: 5

Author(s): Michael A. Arowosegbe*, Oluwamuyiwa T. Amusan, Segun A. Adeola, Oluwatosin B. Adu, Israel A. Akinola, Bimpe F. Ogungbe, Olaposi I. Omotuyi, Gbemisola M. Saibu, Adewale J. Ogunleye, Ramon I. Kanmodi, Nekabari E. Lugbe, Oluwafemi J. Ogunmola, Damilola C. Ajayi, Sedoten O. Ogun, Faith O. Oyende, Ahmed O. Bello, Peter G. Ishola and Patrick E. Obasieke

Affiliation:

• Centre for Biocomputing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo,Nigeria

Keywords: PAK4, kaempferol, docking, MM-GBSA, cancer, Triple Negative Breast Cancer (TNBC).

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.

Cite this article as:

Arowosegbe A. Michael *, Amusan T. Oluwamuyiwa , Adeola A. Segun , Adu B. Oluwatosin , Akinola A. Israel , Ogungbe F. Bimpe , Omotuyi I. Olaposi , Saibu M. Gbemisola , Ogunleye J. Adewale , Kanmodi I. Ramon , Lugbe E. Nekabari , Ogunmola J. Oluwafemi , Ajayi C. Damilola , Ogun O. Sedoten , Oyende O. Faith , Bello O. Ahmed , Ishola G. Peter and Obasieke E. Patrick , Kaempferol as a Potential PAK4 Inhibitor in Triple Negative Breast Cancer: Extra Precision Glide Docking and Free Energy Calculation, Current Drug Discovery Technologies 2020; 17 (5) . https://dx.doi.org/10.2174/1570163816666190823135948