Schüller Andreas, Fechner Uli, Renner Steffen, Franke Lutz, Weber Lutz, Schneider Gisbert
Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Siesmayerstr. 70, D-60323 Frankfurt am Main, Germany.
Comb Chem High Throughput Screen. 2006 Jun;9(5):359-64. doi: 10.2174/138620706777452375.
A virtual screening method is presented that is grounded on a receptor-derived pharmacophore model termed "virtual ligand" or "pseudo-ligand". The model represents an idealized constellation of potential ligand sites that interact with residues of the binding pocket. For rapid virtual screening of compound libraries the potential pharmacophore points of the virtual ligand are encoded as an alignment-free correlation vector, avoiding spatial alignment of pharmacophore features between the pharmacophore query (i.e., the virtual ligand) and the candidate molecule. The method was successfully applied to retrieving factor Xa inhibitors from a Ugi three-component combinatorial library, and yielded high enrichment of actives in a retrospective search for cyclooxygenase-2 (COX-2) inhibitors. The approach provides a concept for "de-orphanizing" potential drug targets and identifying ligands for hitherto unexplored or allosteric binding pockets.
本文提出了一种虚拟筛选方法，该方法基于一种受体衍生的药效团模型，称为“虚拟配体”或“伪配体”。该模型代表了与结合口袋残基相互作用的潜在配体位点的理想化组合。为了对化合物库进行快速虚拟筛选，虚拟配体的潜在药效团点被编码为无对齐相关向量，避免了药效团查询（即虚拟配体）与候选分子之间药效团特征的空间对齐。该方法已成功应用于从乌吉三组分组合库中检索凝血因子Xa抑制剂，并在回顾性搜索环氧合酶-2（COX-2）抑制剂时获得了高活性富集。该方法为“解除”潜在药物靶点的“孤儿”状态以及识别迄今未探索的或变构结合口袋的配体提供了一种概念。
