Protein kinases play a central role in a variety of signal transduction cascades. Their dysfunctions or deregulations are at the origin of severe diseases, especially cancer. The human kinome with more than 500 kinases identified represents a wealth of therapeutic targets. The distinct family of With-No-Lysine (WNK) serine/threonine kinases 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. In fact, it has been shown that key mutations in WNK1 or WNK4 can cause pseudohypoaldosteronism type II. Interestingly, only a few compounds have been found to bind WNK proteins. A recent study identified the first orally bioavailable and highly selective inhibitor (WNK463) of WNK’s catalytic activity. WNK463 is a low-nanomolar binder at all four WNK proteins but has been stopped in preclinical trials due to its safety profile. In this study, we aim to analyze and better understand the binding modes of all public-domain small molecules known to be active towards any of the WNK family member. To do so, we relied on cheminformatics approaches including structure-activity relationships, structure-based molecular docking, and molecular dynamics. In particular, we analyzed the (i) molecular selectivity of known inhibitors when docked in the binding site of each WNK family member, (ii) the dynamic WNK-ligand interactions, and (iii) the prediction performances of cheminformatics techniques to discriminate the most potent WNK inhibitors. Finally, we report on the results of a virtual screening of the ZINC library for identifying new potent and selective WNK inhibitors.

Cheminformatics analysis of WNK-inhibitor interactions

253rd National Meeting (2017)

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