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

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) a...

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Autores principales: Aggarwal, Mayank, Kovalevsky, Andrey Y., Velazquez, Hector, Fisher, S. Zoë, Smith, Jeremy C., McKenna, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391854/
https://www.ncbi.nlm.nih.gov/pubmed/28461893
http://dx.doi.org/10.1107/S2052252516010514
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author Aggarwal, Mayank
Kovalevsky, Andrey Y.
Velazquez, Hector
Fisher, S. Zoë
Smith, Jeremy C.
McKenna, Robert
author_facet Aggarwal, Mayank
Kovalevsky, Andrey Y.
Velazquez, Hector
Fisher, S. Zoë
Smith, Jeremy C.
McKenna, Robert
author_sort Aggarwal, Mayank
collection PubMed
description 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 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. 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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spelling pubmed-53918542017-05-01 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 IUCrJ Research Papers 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 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. 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. International Union of Crystallography 2016-07-22 /pmc/articles/PMC5391854/ /pubmed/28461893 http://dx.doi.org/10.1107/S2052252516010514 Text en © Mayank Aggarwal et al. 2016 http://creativecommons.org/licenses/by/2.0/uk/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Aggarwal, Mayank
Kovalevsky, Andrey Y.
Velazquez, Hector
Fisher, S. Zoë
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
title Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug
title_full Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug
title_fullStr Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug
title_full_unstemmed Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug
title_short Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug
title_sort neutron structure of human carbonic anhydrase ii in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391854/
https://www.ncbi.nlm.nih.gov/pubmed/28461893
http://dx.doi.org/10.1107/S2052252516010514
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