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Title: Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug

Abstract

Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO 2 and HCO 3 , and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with an R cryst of ~16.0%. Presented in this article, along with only the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity ( K i) for both of the drugs against hCA II is similar (~10 n M). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II–MZM determined at cryotemperature andmore » room temperature. Furthermore, this study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.« less

Authors:
 [1];  [1];  [2];  [3];  [2];  [4]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  3. European Spallation Source, Lund (Sweden)
  4. Univ. of Florida, Gainesville, FL (United States)
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1326115
Alternate Identifier(s):
OSTI ID: 1327752
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article: Published Article
Journal Name:
IUCrJ
Additional Journal Information:
Journal Volume: 3; Journal Issue: 5; Journal ID: ISSN 2052-2525
Publisher:
International Union of Crystallography
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; human carbonic anhydrase; acetazolamide; methazolamide; neutron structure; drug binding

Citation Formats

Aggarwal, Mayank, Kovalevsky, Andrey Y., Velazquez, Hector, Fisher, S. Zoe, Smith, Jeremy C., and McKenna, Robert. Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug. United States: N. p., 2016. Web. doi:10.1107/S2052252516010514.
Aggarwal, Mayank, Kovalevsky, Andrey Y., Velazquez, Hector, Fisher, S. Zoe, Smith, Jeremy C., & McKenna, Robert. Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug. United States. doi:10.1107/S2052252516010514.
Aggarwal, Mayank, Kovalevsky, Andrey Y., Velazquez, Hector, Fisher, S. Zoe, Smith, Jeremy C., and McKenna, Robert. Fri . "Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug". United States. doi:10.1107/S2052252516010514.
@article{osti_1326115,
title = {Neutron structure of human carbonic anhydrase II in complex with methazolamide: Mapping the solvent and hydrogen-bonding patterns of an effective clinical drug},
author = {Aggarwal, Mayank and Kovalevsky, Andrey Y. and Velazquez, Hector and Fisher, S. Zoe and Smith, Jeremy C. and McKenna, Robert},
abstractNote = {Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO2 and HCO3–, and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with an Rcryst of ~16.0%. Presented in this article, along with only the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity (Ki) for both of the drugs against hCA II is similar (~10 nM). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II–MZM determined at cryotemperature and room temperature. Furthermore, this study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.},
doi = {10.1107/S2052252516010514},
journal = {IUCrJ},
number = 5,
volume = 3,
place = {United States},
year = {Fri Jul 22 00:00:00 EDT 2016},
month = {Fri Jul 22 00:00:00 EDT 2016}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1107/S2052252516010514

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Cited by: 3 works
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