Computational and functional analyses of a small-molecule binding site in ROMK

Biophysical Journal
Daniel R SwaleJerod S Denton

Abstract

The renal outer medullary potassium channel (ROMK, or Kir1.1, encoded by KCNJ1) critically regulates renal tubule electrolyte and water transport and hence blood volume and pressure. The discovery of loss-of-function mutations in KCNJ1 underlying renal salt and water wasting and lower blood pressure has sparked interest in developing new classes of antihypertensive diuretics targeting ROMK. The recent development of nanomolar-affinity small-molecule inhibitors of ROMK creates opportunities for exploring the chemical and physical basis of ligand-channel interactions required for selective ROMK inhibition. We previously reported that the bis-nitro-phenyl ROMK inhibitor VU591 exhibits voltage-dependent knock-off at hyperpolarizing potentials, suggesting that the binding site is located within the ion-conduction pore. In this study, comparative molecular modeling and in silico ligand docking were used to interrogate the full-length ROMK pore for energetically favorable VU591 binding sites. Cluster analysis of 2498 low-energy poses resulting from 9900 Monte Carlo docking trajectories on each of 10 conformationally distinct ROMK comparative homology models identified two putative binding sites in the transmembrane pore that were subs...Continue Reading

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Citations

May 26, 2015·Expert Opinion on Therapeutic Patents·Alma MartelliVincenzo Calderone
Dec 31, 2015·Tissue Barriers·Klaus W BeyenbachJerod Denton
May 6, 2015·Channels·Sujay V KharadeJerod S Denton
May 18, 2016·ACS Chemical Neuroscience·Daniel R SwaleJerod S Denton
Oct 28, 2017·Future Medicinal Chemistry·Birgit T Priest, Alexander Pasternak
Apr 8, 2021·American Journal of Physiology. Cell Physiology·C David Weaver, Jerod S Denton
Feb 20, 2018·ACS Medicinal Chemistry Letters·Matthew F SammonsJerod S Denton

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