Unite de Bioinformatique Structurale, Institut Pasteur, 26 rue du Dr Roux, 75015 Paris, France.
J Chem Inf Model. 2010 Jun 28;50(6):992-1004. doi: 10.1021/ci900507g.
In the early stage of drug discovery programs, when the structure of a complex involving a target and a small molecule is available, structure-based virtual ligand screening methods are generally preferred. However, ligand-based strategies like shape-similarity search methods can also be applied. Shape-similarity search methods consist in exploring a pseudo-binding-site derived from the known small molecule used as a reference. Several of these methods use conformational sampling algorithms which are also shared by corresponding docking methods: for example Surflex-dock/Surflex-sim, FlexX/FlexS, ICM, and OMEGA-FRED/OMEGA-ROCS. Using 11 systems issued from the challenging "own" subsets of the Directory of Useful Decoys (DUD-own), we evaluated and compared the performance of the above-cited programs in terms of molecular alignment accuracy, enrichment in active compounds, and enrichment in different chemotypes (scaffold-hopping). Since molecular alignment is a crucial aspect of performance for the different methods, we have assessed its impact on enrichment. We have also illustrated the paradox of retrieving active compounds with good scores even if they are inaccurately positioned. Finally, we have highlighted possible positive aspects of using shape-based approaches in drug-discovery protocols when the structure of the target in complex with a small molecule is known.
在药物发现计划的早期阶段，当涉及目标和小分子的复杂结构可用时，通常首选基于结构的虚拟配体筛选方法。然而，也可以应用基于配体的策略，如形状相似性搜索方法。形状相似性搜索方法包括探索源自用作参考的已知小分子的伪结合位点。其中有几种方法使用构象采样算法，这些算法也与相应的对接方法共享：例如 Surflex-dock/Surflex-sim、FlexX/FlexS、ICM 和 OMEGA-FRED/OMEGA-ROCS。我们使用来自具有挑战性的“自有”目录的 11 个系统（DUD-own）评估并比较了上述程序在分子对准精度、活性化合物富集和不同化学型（支架跳跃）富集方面的性能。由于分子对准是不同方法性能的关键方面，我们评估了它对富集的影响。我们还说明了即使化合物位置不准确，也能检索到具有良好得分的活性化合物的悖论。最后，当已知小分子与靶标复合物的靶标结构时，我们强调了在药物发现方案中使用基于形状的方法的可能积极方面。
