Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec H3A 0B8, Canada.
J Med Chem. 2012 Jul 26;55(14):6306-15. doi: 10.1021/jm3002839. Epub 2012 Jul 17.
Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.
我们的对接程序 Fitted，在我们的计算平台 Forecaster 中实现，已被修改为进行共价抑制剂的自动化虚拟筛选。使用该程序的修改版本，对选定的命中进行虚拟筛选和基于对接的进一步优化，导致鉴定脯氨酰寡肽酶活性的潜在共价可逆抑制剂。经过目视检查，选择一个虚拟命中分子及其四个类似物进行合成，并在一到五个化学步骤中完成。对重组 POP 和 FAPα 酶、细胞提取物和活细胞的生物学评估表明，对 POP 的高活性和选择性高于 FAPα 和 DPPIV。三种化合物甚至在完整的活人体细胞中表现出高纳摩尔抑制活性和可接受的代谢稳定性。这一小组分子还表明，与配体/蛋白质复合物的共价结合和/或几何约束可能导致生物活性增加。
