Schüttelkopf Alexander W, Andersen Ole A, Rao Francesco V, Allwood Matthew, Rush Christina L, Eggleston Ian M, van Aalten Daan M F
Division of Molecular Microbiology and Division of Biological Chemistry and Molecular Microbiology, College of Life Sciences, University of Dundee , Dow Street, Dundee, DD1 5EH, Scotland.
ACS Med Chem Lett. 2011 Mar 23;2(6):428-32. doi: 10.1021/ml200008b. eCollection 2011 Jun 9.
Chitinases of the GH18 family play important roles in a variety of pathogenic organisms and have also been shown to be involved in human asthma progression, making these enzymes potential drug targets. While a number of potent GH18 chitinase inhibitors have been described, in general, these compounds suffer from limited synthetic accessibility or unfavorable medicinal-chemical properties, making them poor starting points for the development of chitinase-targeted drugs. Exploiting available structural data, we have rationally designed bisdionin C, a submicromolar inhibitor of GH18 enzymes, that possesses desirable druglike properties and tractable chemical synthesis. A crystallographic structure of a chitinase-bisdionin C complex shows the two aromatic systems of the ligand interacting with two conserved tryptophan residues exposed in the active site cleft of the enzyme, while at the same time forming extensive hydrogen-bonding interactions with the catalytic machinery. The observed mode of binding, together with inhibition data, suggests that bisdionin C presents an attractive starting point for the development of specific inhibitors of bacterial-type, but not plant-type, GH 18 chitinases.
GH18家族的几丁质酶在多种致病生物中发挥重要作用，并且已被证明与人类哮喘的进展有关，这使得这些酶成为潜在的药物靶点。虽然已经描述了许多有效的GH18几丁质酶抑制剂，但总体而言，这些化合物存在合成可达性有限或药物化学性质不佳的问题，使其成为开发以几丁质酶为靶点的药物的不良起始点。利用现有的结构数据，我们合理设计了双二酮宁C，一种GH18酶的亚微摩尔抑制剂，它具有理想的类药物性质和易于处理的化学合成方法。几丁质酶 - 双二酮宁C复合物的晶体结构显示，配体的两个芳香体系与酶活性位点裂隙中暴露的两个保守色氨酸残基相互作用，同时与催化机制形成广泛的氢键相互作用。观察到的结合模式以及抑制数据表明，双二酮宁C为开发细菌型而非植物型GH 18几丁质酶的特异性抑制剂提供了一个有吸引力的起始点。
