例如:"lncRNA", "apoptosis", "WRKY"

Insights on small molecule binding to the Hv1 proton channel from free energy calculations with molecular dynamics simulations.

Sci Rep. 2020 Aug 12;10(1):13587
Victoria T Lim 1 , Andrew D Geragotelis 1 , Nathan M Lim 2 , J Alfredo Freites 1 , Francesco Tombola 3 , David L Mobley 4 , Douglas J Tobias 5
Victoria T Lim 1 , Andrew D Geragotelis 1 , Nathan M Lim 2 , J Alfredo Freites 1 , Francesco Tombola 3 , David L Mobley 4 , Douglas J Tobias 5
+ et al

[No authors listed]

Author information
  • 1 Department of Chemistry, University of California, Irvine, CA, 92697, USA.
  • 2 Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA.
  • 3 Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, 92697, USA.
  • 4 Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697, USA. dmobley@mobleylab.org.
  • 5 Chao Family Comprehensive Cancer Center, University of California, Irvine, CA, 92697, USA. dtobias@uci.edu.

摘要


Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we computed relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We used alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model and shed light on the preferred tautomeric state of the channel blocker. This work lays the groundwork for future studies on adapting the blocker molecule for more effective inhibition of Hv1.