9FPS

Crystal structure of carbonic anhydrase II with methyl 4-methylsulfanyl-3-sulfamoyl-benzoate

これはPDB形式変換不可エントリーです。

9FPS の概要

• エントリーDOI: 10.2210/pdb9fps/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, methyl 4-methylsulfanyl-3-sulfamoyl-benzoate, ... (5 entities in total)
• 機能のキーワード: drug design, carbonic anhydrase, benzenesulfonamide, lyase-lyase inhibitor complex, lyase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29955.24

構造登録者

Smirnov, A.,Manakova, E.N.,Grazulis, S.,Paketuryte, V. (登録日: 2024-06-13, 公開日: 2025-06-25, 最終更新日: 2025-10-08)

主引用文献

Zaksauskas, A.,Paketuryte-Latve, V.,Jankunaite, A.,Capkauskaite, E.,Becart, Y.,Smirnov, A.,Pospisilova, K.,Leitans, J.,Brynda, J.,Kazaks, A.,Baranauskiene, L.,Manakova, E.,Grazulis, S.,Kairys, V.,Tars, K.,Rezacova, P.,Matulis, D.
Affinity and Selectivity of Protein-Ligand Recognition: A Minor Chemical Modification Changes Carbonic Anhydrase Binding Profile.
J.Med.Chem., 68:17752-17773, 2025

PubMed Abstract: Discovery of small-molecule drugs relies on their strong binding affinity compared to nontarget proteins, thus possessing selectivity. Minor chemical structure changes usually exhibit little change in the compound efficacy, with rare exceptions. We developed a series of nearly 50 -substituted benzenesulfonamides and experimentally measured their interactions with the 12 catalytically active human carbonic anhydrase (CA) isozymes. Inhibitors were designed using seven different substituent groups, including 4--substituted 3-sulfamoyl benzoates and benzamides, 4--substituted 3-sulfamoyl benzoates and benzamides, 4--substituted 3-sulfamoyl benzoates and benzamides, and 4-amino-substituted benzamides. The oxidation state of sulfur at the position significantly influenced the compound's affinity for CAIX, a target for anticancer drugs, demonstrating affinities hundreds of thousands of times stronger than related compounds. Coupled with X-ray crystal structures and molecular docking, the relationship between structure and thermodynamics offers insights into how small changes in the structure lead to significant changes in affinity for drug design.

PubMed: 40801814
DOI: 10.1021/acs.jmedchem.5c01421

実験手法

X-RAY DIFFRACTION (1.39 Å)