Pharmacoinformatics and molecular dynamic simulation studies to identify potential small-molecule inhibitors of WNK-SPAK/OSR1 signaling that mimic the RFQV motifs of WNK kinases

The WNK-SPAK/OSR1 signaling is a complex of serine and threonine protein kinases that involves in the regulation of human blood pressure. The WNK kinases phosphorylate and activate SPAK and OSR1 kinases through the interaction of RFQV motifs of WNK kinases with the C-terminal domains of SPAK and OSR1. Upon phosphorylation, SPAK and OSR1 phosphorylate key ion co-transporters such as Na+-[K+]-2Cl(-) (NKCC1-2) and K+-Cl- (KCC1-4), which are essential for electrolytes balance and blood pressure regulation. Targeting the binding site of the RFQV motifs of WNK kinases on the C-terminal domain (CTD) of SPAK and OSR1 has emerged as a valuable approach to inhibit the WNK-SPAK/OSR1 signaling pathway. Herein, an effort has been intended to pinpoint non-peptidic small-molecules that could disrupt the binding of SPAK/OSR1 to WNK kinases, hence, inhibit the SPAK and OSR1 phosphorylation and activation by WNK kinases through pharmacoinformatics and molecular dynamic simulation methodologies. A sequential structure-based virtual screening of a focus protein-protein interaction chemical library composed of 11,870 compounds lead to the identification of three compounds having good lead-compound properties with respect to their predicted inhibitory constants, pharmacophore fit scores, binding affinities, ADME-T parameters, drug-likeness properties and ligand efficiency metrics. The mechanism of interaction and binding stability of these compounds to OSR1-CTD were confirmed using molecular docking and dynamic simulation studies. Hence, the identified compounds may have therapeutic potential as novel antihypertensive agents subjected to experimental validation. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.