Cheminformatics Analysis of Dynamic WNK-Inhibitor Interactions.

The With-No-Lysine (WNK) serine/threonine kinase family constitutes a unique and distinctive branch of the kinome. The four proteins of this family (WNK1/2/3/4) are involved in blood pressure regulation, body fluid, and electrolyte homeostasis. Herein, we modeled and analyzed the binding modes of all publicly-available small orthosteric and allosteric binders (including WNK463 and WNK467) experimentally tested towards any of the WNK family member. To do so, we relied on state-of-the-art cheminformatics approaches including structure-based molecular docking and molecular dynamics simulations. In particular, we computed and analyzed the (i) molecular selectivity of known inhibitors when docked in the binding site of each WNK family member, (ii) the dynamic WNK-inhibitor interactions at both orthosteric and allosteric sites to derive new structure-activity relationships, and (iii) the key specific interactions present in each binding site. This study reports on the first, cheminformatics-powered analysis of the entire chemical space of known WNK inhibitors. We discuss the conservation of critical WNK-inhibitor interactions and the existence of isoform-specific interactions that could enable the rational design of more potent and selective WNK binders.