Dipartimento Farmaco-Chimico, University of Bari, Via Orabona 4, 70125, Bari, Italy.
J Comput Aided Mol Des. 2010 Feb;24(2):117-29. doi: 10.1007/s10822-010-9320-1. Epub 2010 Feb 11.
A series of 27 benzamidine inhibitors covering a wide range of biological activity and chemical diversity was analysed to derive a Linear Interaction Energy in Continuum Electrostatics (LIECE) model for analysing the thrombin inhibitory activity. The main interactions occurring at the thrombin binding site and the preferred binding conformations of inhibitors were explicitly biased by including into the LIECE model 10 compounds extracted from X-ray solved thrombin-inhibitor complexes available from the Protein Data Bank (PDB). Supported by a robust statistics (r(2) = 0.698; q(2) = 0.662), the LIECE model was successful in predicting the inhibitory activity for about 76% of compounds (r (ext) (2) > or = 0.600) from a larger external test set encompassing 88 known thrombin inhibitors and, more importantly, in retrieving, at high sensitivity and with better performance than docking and shape-based methods, active compounds from a thrombin combinatorial library of 10240 mimetic chemical products. The herein proposed LIECE model has the potential for successfully driving the design of novel thrombin inhibitors with benzamidine and/or benzamidine-like chemical structure.
分析了一系列涵盖广泛生物活性和化学多样性的 27 种苯甲脒抑制剂，以得出用于分析凝血酶抑制活性的线性相互作用静电（LIECE）模型。通过将从蛋白质数据库（PDB）中可用的 X 射线解决的凝血酶抑制剂复合物中提取的 10 种化合物纳入 LIECE 模型，明确偏向于发生在凝血酶结合部位的主要相互作用和抑制剂的首选结合构象。该模型得到了强大统计学（r（2）= 0.698；q（2）= 0.662）的支持，成功地预测了更大外部测试集中约 76％化合物的抑制活性（r（ext）（2）≥0.600），该测试集包含 88 种已知的凝血酶抑制剂，更重要的是，与对接和基于形状的方法相比，该模型以更高的灵敏度和更好的性能从包含 10240 种模拟化学产品的凝血酶组合文库中检索到了活性化合物。在此提出的 LIECE 模型具有成功设计具有苯甲脒和/或苯甲脒样化学结构的新型凝血酶抑制剂的潜力。
