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

Aggarwal, Mayank; Kovalevsky, Andrey Y.; Velazquez, Hector; Fisher, S. Zoë; Smith, Jeremy C.; McKenna, Robert

doi:10.1107/S2052252516010514

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

Journal Article · Fri Jul 22 00:00:00 EDT 2016 · IUCrJ

DOI:https://doi.org/10.1107/S2052252516010514· OSTI ID:1326115

Aggarwal, Mayank; Kovalevsky, Andrey Y.; Velazquez, Hector; Fisher, S. Zoë; Smith, Jeremy C.; McKenna, Robert

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 and room temperature. 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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1326115

Alternate ID(s):: OSTI ID: 1327752

Journal Information:: IUCrJ, Journal Name: IUCrJ Journal Issue: 5 Vol. 3; ISSN 2052-2525; ISSN IUCRAJ

Publisher:: International Union of Crystallography (IUCr)Copyright Statement

Country of Publication:: United Kingdom

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
acetazolamide
drug binding
human carbonic anhydrase
methazolamide
neutron structure

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

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