ヒト炭酸脱水酵素Iとスルホンアミド薬3種の複合体精密構造解析
Three complexes of N-unsubstituted sulfonamide drugs bound to human carbonic anhydrase I (HCAI) were structurally characterized by X-ray crystallography at 2 Å resolution. All drug molecules occupy the enzyme active site, where they displace the zinc-coordinated solvent molecule present in the native form. Despite this common feature, the sulfamido groups adopt distinct orientations relative to the essential zinc ion across the three complexes. The active-site loop comprising Leu198, Thr199, and His200 undergoes notable atomic displacements and forms intramolecular hydrogen bonds upon drug binding, implicating this region in inhibitor recognition. Differences in sulfamido orientation and inhibitory potency among the drugs are attributed to these interactions combined with active-site electrostatic requirements. Binding of methazolamide, but not the other two sulfonamides, disrupts a hydrogen-bond network involving His200 and His67, providing the first crystallographic indication of His200 participation in HCAI inhibition. An additional role for Thr199 in discriminating between substrate and inhibitor binding at elevated pH is also proposed.
Sulfonamide drugs displace the zinc-coordinated water molecule in the HCAI active site and form hydrogen bonds with the Leu198-Thr199-His200 loop, thereby inhibiting enzymatic activity; methazolamide additionally disrupts a His200-His67 hydrogen-bond network.
This is basic research at the cellular or molecular level. For human application, inhalation is the most promising delivery route, but inhalation carries explosion risk and concentration matters (empirical LFL of 10%; high-concentration devices are not recommended).
See also:
https://h2-papers.org/en/papers/7932756