4.7 Article

Investigating specificity of the anti-hypertensive inhibitor WNK463 against With-No-Lysine kinase family isoforms via multiscale simulations

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 38, Issue 5, Pages 1306-1321

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2019.1602079

Keywords

With-No-Lysine kinase; molecular mechanics Poisson-Boltzmann surface area (MMPBSA); molecular dynamics; free energy

Funding

  1. Department of Biotechnology, Govt. of India [BT/RLF/Re-entry/40/2014]
  2. Department of Science and Technology, Govt. of India [ECR/2017/000010]
  3. Indian Institute of Technology Indore

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The With-No-Lysine (WNK) kinase family plays a significant role in regulating cation-chloride cotransporters, blood pressure and body fluid homeostasis. Mutations in the gene of WNK family, especially in WNK1 and WNK4 are responsible for pseudohypoaldosteronism type II (PHAII), characterized by hypertension. The selective inhibition of WNK1 over other isoforms has created an immense challenge in the design of an ATP competitive inhibitor due to their high conservatism. In this work, we have compared the selectivity of the inhibitor WNK463, which was designed for WNK1 with other WNK family isoforms by comprehensive molecular modeling, docking and molecular dynamics simulations in conjunction with the Molecular Mechanics Poisson-Boltzmann Surface Area method. Our calculations show that the affinity of the inhibitor decreases in the order WNK2 > WNK1 > WNK3 > WNK4, in agreement with the experiment. Our study reveals that the inhibitor is most selective to WNK2 due to decreased polar solvation and configurational entropy compared to other isoforms. Furthermore, our analyses indicated that the nonpolar contribution from the hydrophobic residues and hydrogen bonds in the hinge region gatekeeper residue Met(304) of WNK1 and its equivalent residue from other kinases played a critical role in stabilizing the inhibitor against WNK kinases. Residues Lys(233), Met(304), Phe(356) and Leu(369) of WNK1 were the essential residue differences compared to other isoforms that led to specific interactions thereby forming the basis of molecular binding pattern of binding interactions. Overall, we have identified conserved WNK-inhibitor interactions and elucidated isoform-specific interactions that could be exploited in the design of more potent and selective WNK inhibitors.

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