Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, SA, Italy.
Eur J Med Chem. 2013 Jul;65:464-76. doi: 10.1016/j.ejmech.2013.05.016. Epub 2013 May 23.
In the last decade Hsp90 inhibitors have emerged as attractive candidates for the development of new potent anticancer therapeutics. In order to identify novel agents able to block the chaperone activity, following a structure-based approach, we used in silico screening to direct the synthesis of potential inhibitors bearing the triazole scaffold, a widespread motif in drug-like molecules. Docking results, performed on a larger collection of dimeric and trimeric triazole derivatives, suggested the synthesis of some molecules showing different calculated binding energies and modes. Surface Plasmon Resonance Binding assay, performed on the synthesized compounds, allow to identify a series of molecules able to potently interact with the target enzyme and to disclose an interesting hit: compound 2b showed to interact with the ATP binding site in the N-terminus domain of Hsp90 and to efficiently inhibit the chaperone activity.
在过去的十年中，Hsp90 抑制剂已成为开发新型强效抗癌治疗药物的有吸引力的候选药物。为了找到能够阻断伴侣活性的新型试剂，我们采用基于结构的方法，通过计算机筛选来指导具有三唑骨架的潜在抑制剂的合成，三唑骨架是药物样分子中广泛存在的结构基序。对更大的二聚体和三聚体三唑衍生物集合进行对接结果表明，需要合成一些显示不同计算结合能和模式的分子。对合成化合物进行表面等离子体共振结合测定，可鉴定出一系列能够与靶酶有效相互作用并揭示出有趣的化合物：化合物 2b 显示与 Hsp90 N 端结构域的 ATP 结合位点相互作用，并有效地抑制伴侣活性。
