Schnecke V, Kuhn L A
Department of Biochemistry, Michigan State University, East Lansing 48824-1319, USA.
Proc Int Conf Intell Syst Mol Biol. 1999:242-51.
Screening for potential ligands and docking them into the binding sites of proteins is one of the main tasks in computer-aided drug design. Despite the progress in computational power, it remains infeasible to model all the factors involved in molecular recognition, especially when screening databases of more than 100,000 compounds. While ligand flexibility is considered in most approaches, the model of the binding site is rather simplistic, with neither solvation nor induced complementary usually taken into consideration. We present results for screening different databases for HIV-1 protease ligands with our tool Slide, and investigate the extent to which binding-site conformation, solvation, and template representation generate bias. The results suggest a strategy for selecting the optimal binding-site conformation, for cases in which more than one independent structure is available, and selecting a representation of that binding site that yields reproducible results and the identification of known ligands.
筛选潜在配体并将其对接至蛋白质的结合位点是计算机辅助药物设计的主要任务之一。尽管计算能力有所进步，但对分子识别中涉及的所有因素进行建模仍然不可行，尤其是在筛选超过100,000种化合物的数据库时。虽然大多数方法都考虑了配体的灵活性，但结合位点的模型相当简单，通常既不考虑溶剂化也不考虑诱导互补。我们展示了使用我们的工具Slide筛选不同数据库中的HIV-1蛋白酶配体的结果，并研究了结合位点构象、溶剂化和模板表示产生偏差的程度。结果表明了一种策略，即在有多个独立结构可用的情况下选择最佳结合位点构象，并选择能产生可重复结果并识别已知配体的该结合位点表示形式。
