3KKU

Cruzain in complex with a non-covalent ligand

3KKU の概要

• エントリーDOI: 10.2210/pdb3kku/pdb
• 分子名称: Cruzipain, N-[2-(1H-benzimidazol-2-yl)ethyl]-2-(2-bromophenoxy)acetamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: autocatalytic cleavage, glycoprotein, protease, thiol protease, zymogen, hydrolase
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23836.24

構造登録者

Ferreira, R.S.,Eidam, O.,Shoichet, B.K. (登録日: 2009-11-06, 公開日: 2010-07-07, 最終更新日: 2024-11-27)

主引用文献

Ferreira, R.S.,Simeonov, A.,Jadhav, A.,Eidam, O.,Mott, B.T.,Keiser, M.J.,McKerrow, J.H.,Maloney, D.J.,Irwin, J.J.,Shoichet, B.K.
Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors.
J.Med.Chem., 53:4891-4905, 2010

PubMed Abstract: Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99% of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1% of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone.

PubMed: 20540517
DOI: 10.1021/jm100488w

実験手法

X-RAY DIFFRACTION (1.28 Å)