"To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation
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 II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. In conclusion, this study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.
- Authors:
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1548734
- Alternate Identifier(s):
- OSTI ID: 1474662
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Published Article
- Journal Name:
- Structure
- Additional Journal Information:
- Journal Name: Structure Journal Volume: 26 Journal Issue: 3; Journal ID: ISSN 0969-2126
- Publisher:
- Elsevier
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; human carbonic anhydrase; brinzolamide; dorzolamide; ethoxzolamide; perdeuteration; neutron crystallography; hydrogen bonding; drug binding; MD simulations
Citation Formats
Kovalevsky, Andrey, Aggarwal, Mayank, Velazquez, Hector, Cuneo, Matthew J., Blakeley, Matthew P., Weiss, Kevin L., Smith, Jeremy C., Fisher, S. Zoë, and McKenna, Robert. "To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation. United Kingdom: N. p., 2018.
Web. doi:10.1016/j.str.2018.01.006.
Kovalevsky, Andrey, Aggarwal, Mayank, Velazquez, Hector, Cuneo, Matthew J., Blakeley, Matthew P., Weiss, Kevin L., Smith, Jeremy C., Fisher, S. Zoë, & McKenna, Robert. "To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation. United Kingdom. https://doi.org/10.1016/j.str.2018.01.006
Kovalevsky, Andrey, Aggarwal, Mayank, Velazquez, Hector, Cuneo, Matthew J., Blakeley, Matthew P., Weiss, Kevin L., Smith, Jeremy C., Fisher, S. Zoë, and McKenna, Robert. Thu .
""To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation". United Kingdom. https://doi.org/10.1016/j.str.2018.01.006.
@article{osti_1548734,
title = {"To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation},
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},
abstractNote = {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. In conclusion, this study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.},
doi = {10.1016/j.str.2018.01.006},
journal = {Structure},
number = 3,
volume = 26,
place = {United Kingdom},
year = {Thu Mar 01 00:00:00 EST 2018},
month = {Thu Mar 01 00:00:00 EST 2018}
}
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https://doi.org/10.1016/j.str.2018.01.006
https://doi.org/10.1016/j.str.2018.01.006
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Cited by: 26 works
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Works referencing / citing this record:
Engineered Carbonic Anhydrase VI-Mimic Enzyme Switched the Structure and Affinities of Inhibitors
journal, September 2019
- Kazokaitė, Justina; Kairys, Visvaldas; Smirnovienė, Joana
- Scientific Reports, Vol. 9, Issue 1
Engineered Carbonic Anhydrase VI-Mimic Enzyme Switched the Structure and Affinities of Inhibitors
text, January 2019
- Kazokaitė, Justina; Kairys, Visvaldas; Smirnovienė, Joana
- Deutsches Elektronen-Synchrotron, DESY, Hamburg
Engineered Carbonic Anhydrase VI-Mimic Enzyme Switched the Structure and Affinities of Inhibitors
journal, September 2019
- Kazokaitė, Justina; Kairys, Visvaldas; Smirnovienė, Joana
- Scientific Reports, Vol. 9, Issue 1
Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase
journal, May 2019
- Gerlits, Oksana; Kong, Xiaotian; Cheng, Xiaolin
- Journal of Biological Chemistry, Vol. 294, Issue 27
Neutron scattering in the biological sciences: progress and prospects
journal, December 2018
- Ashkar, Rana; Bilheux, Hassina Z.; Bordallo, Heliosa
- Acta Crystallographica Section D Structural Biology, Vol. 74, Issue 12
Biophysical, Biochemical, and Cell Based Approaches Used to Decipher the Role of Carbonic Anhydrases in Cancer and to Evaluate the Potency of Targeted Inhibitors
journal, July 2018
- Mboge, Mam Y.; Kota, Anusha; McKenna, Robert
- International Journal of Medicinal Chemistry, Vol. 2018
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