Chem-Bio Informatics Journal
Online ISSN : 1347-0442
Print ISSN : 1347-6297
ISSN-L : 1347-0442
Communication
Docking simulation of fragment library compounds to find new leads for specific WNK kinase inhibitors
Nae SaitoYukio TadaTakayoshi OkabeTetsuo Nagano
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2017 Volume 17 Pages 30-33

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Abstract

Pseudohypoaldosteronism type II has been known as a rare autosomal dominant disorder caused by WNK1 [with no K (lysine) protein kinase-1] or WNK4. These serine/threonine kinases have unusual structures with a back pocket located just behind the ATP binding site. Moreover, a lysine residue (Lys 233 in WNK1) in a glycine-rich loop plays a key role in their activity. In this work, we performed docking simulations of about 9,000 compounds from a fragment library with the back pocket of WNK1 in order to discover candidate lead compounds for development of specific inhibitors. Based on binding energy index, we selected β-tetralone (compound 5) as a lead structure that interacts with the back pocket, but not with the hinge region of WNK1. Guided by the four predicted docking patterns of β-tetralone with the back pocket, we designed four derivatives A-D that were expected to form hydrogen bonds with Lys 233. Docking studies indicated that these derivatives interact selectively with Lys 233, but not with the hinge region. These compounds are considered potential lead compounds for developing selective WNK inhibitors.

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