TargetEx Ltd., Madách I. u. 31/2, 2120 Dunakeszi, Hungary.
Molecules. 2021 Sep 15;26(18):5593. doi: 10.3390/molecules26185593.
Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach in early drug discovery. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compounds' databases. This approach can be combined with physico-chemical parameter and diversity filtering, bioisosteric replacements, and fragment-based approaches for performing a first round biological screening. Our objectives were to investigate the combination of 2D similarity search with various 3D ligand and structure-based methods for hit expansion and validation, in order to increase the hit rate and novelty. In the present account, six case studies are described and the efficiency of mixing is evaluated. While sequentially combined 2D/3D similarity approach increases the hit rate significantly, sequential combination of 2D similarity with pharmacophore model or 3D docking enriched the resulting focused library with novel chemotypes. Parallel integrated approaches allowed the comparison of the various 2D and 3D methods and revealed that 2D similarity-based and 3D ligand and structure-based techniques are often complementary, and their combinations represent a powerful synergy. Finally, the lessons we learnt including the advantages and pitfalls of the described approaches are discussed.
从商业库中快速进行针对目标的虚拟库选择是早期药物发现中一种有吸引力且具有成本效益的方法。如果有活性化合物的结构，则可以在数百万种化合物的数据库上进行快速的 2D 相似性搜索。这种方法可以与物理化学参数和多样性过滤、生物等排替换以及基于片段的方法结合使用，以进行第一轮生物筛选。我们的目标是研究 2D 相似性搜索与各种 3D 配体和基于结构的方法相结合，以进行命中扩展和验证，从而提高命中率和新颖性。在本报告中，描述了六个案例研究，并评估了混合的效率。虽然顺序组合的 2D/3D 相似性方法显著提高了命中率，但与药效团模型或 3D 对接的顺序组合使所得的聚焦库中富含新型化学型。并行集成方法允许比较各种 2D 和 3D 方法，并表明基于 2D 相似性的方法和基于 3D 配体和结构的技术通常是互补的，它们的组合代表了强大的协同作用。最后，讨论了我们所学到的经验教训，包括所描述方法的优点和缺点。
