Screening of Phytochemicals from Medicinal Plants for WNK-1 Inhibition In silico: Potential Anti-cancer Therapeutics

Phytochemicals for cancer reversal has been known for several millennia. With WNK-1 close link to cancer pathology has rendered it attractive target in anticancer drug discovery. Molecular in silico docking of phytochemicals to target WNK-1 protein paves way to identifying lead entities for clinical applications. This computational method to investigate phytochemicals as potential WNK-1 inhibitors was attempted to validate their anticancer activity. WNK-1 (PDB ID: 5TF9) 3D structure from RSCB Protein Data Bank with 2.50Å resolution was retrieved. PyMOL was used to stabilize and adjust it to human physiology adding required hydrogen entities at appropriate positions. Identified phytochemical 3D structure was downloaded from PubChem for docking via PyRx software in 213, 163, 177 Å grid box. The best inhibitor was one with strong ligand binding to WNK-1 forming stable complex. Swiss ADME analysis applied identified those with < 5 Hbond donors, < 500 Dalton molecular weight, < 5 H acceptors and < 5 Q Plog Po/w. The two amino acids Asp465 and Asn463 of protein WNK-1 contributed to binding with ligands. Oleuropein aglycone and Dioscin with strong binding to WNK-1 at energies of -18.3 and -14.3 respectively with highest WNK-1 inhibitory potential are reported. They were followed by Epigallocatechin gallate, Naringenin and Quercetin as inhibitors with binding energy of -8.4 kcal/mol, forming a stable complex to WNK-1. The standard inhibitor WNK463 recorded ∆G of -8.9 kcal/mol. Oleuropein aglycone and Dioscin exhibited strong binding characteristics to WNK-1 and so these molecules could be repurposed for cancer treatment.