7JO3

Carbonic Anhydrase IX Mimic Complexed with N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)pivalamide

7JO3 の概要

• エントリーDOI: 10.2210/pdb7jo3/pdb
• 分子名称: Carbonic anhydrase 2, ZINC ION, 2,2-dimethyl-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)propanamide, ... (5 entities in total)
• 機能のキーワード: carbonic anhydrase, ca inhibitor, structure guided drug design, carbonic anhydrase ii, carbonic anhydrase ix, caii, caix, sulfonamide, lyase, lyase-inhibitor complex, lyase/inhibitor
• 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: 29608.75

構造登録者

Andring, J.T.,McKenna, R. (登録日: 2020-08-05, 公開日: 2020-11-04, 最終更新日: 2023-10-18)

主引用文献

Andring, J.T.,Fouch, M.,Akocak, S.,Angeli, A.,Supuran, C.T.,Ilies, M.A.,McKenna, R.
Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X-Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone.
J.Med.Chem., 63:13064-13075, 2020

PubMed Abstract: This study provides a structure-activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.

PubMed: 33085484
DOI: 10.1021/acs.jmedchem.0c01390

実験手法

X-RAY DIFFRACTION (1.454 Å)