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"To Be or Not to Be" Protonated : Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation

Kovalevsky, Andrey; Aggarwal, Mayank; Velazquez, Hector; Cuneo, Matthew J.; Blakeley, Matthew P.; Weiss, Kevin L.; Smith, Jeremy C.; Fisher, S. Zoë LU and McKenna, Robert (2018) In Structure
Abstract

Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA... (More)

Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX. Kovalevsky et al. used macromolecular neutron crystallography and molecular dynamics simulations to obtain a detailed picture of clinical inhibitors binding to human carbonic anhydrase II. The study visualized hydrogen atom positions, revealing protonation/deprotonation events and intricate hydrogen-bonding networks, providing insights for drug design.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Brinzolamide, Dorzolamide, Drug binding, Ethoxzolamide, Human carbonic anhydrase, Hydrogen bonding, MD simulations, Neutron crystallography, Perdeuteration
in
Structure
publisher
Cell Press
external identifiers
  • scopus:85041659207
ISSN
0969-2126
DOI
10.1016/j.str.2018.01.006
language
English
LU publication?
yes
id
1a0633a3-594e-4e4d-b8be-8c256cce745d
date added to LUP
2018-02-22 07:48:57
date last changed
2018-05-29 10:35:24
@article{1a0633a3-594e-4e4d-b8be-8c256cce745d,
  abstract     = {<p>Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX. Kovalevsky et al. used macromolecular neutron crystallography and molecular dynamics simulations to obtain a detailed picture of clinical inhibitors binding to human carbonic anhydrase II. The study visualized hydrogen atom positions, revealing protonation/deprotonation events and intricate hydrogen-bonding networks, providing insights for drug design.</p>},
  author       = {Kovalevsky, Andrey and Aggarwal, Mayank and Velazquez, Hector and Cuneo, Matthew J. and Blakeley, Matthew P. and Weiss, Kevin L. and Smith, Jeremy C. and Fisher, S. Zoë and McKenna, Robert},
  issn         = {0969-2126},
  keyword      = {Brinzolamide,Dorzolamide,Drug binding,Ethoxzolamide,Human carbonic anhydrase,Hydrogen bonding,MD simulations,Neutron crystallography,Perdeuteration},
  language     = {eng},
  month        = {02},
  publisher    = {Cell Press},
  series       = {Structure},
  title        = {"To Be or Not to Be" Protonated : Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation},
  url          = {http://dx.doi.org/10.1016/j.str.2018.01.006},
  year         = {2018},
}