Graduate Program in Chemistry and Chemical Biology, University of California San Francisco, California 94158, USA.
J Med Chem. 2010 Jul 8;53(13):4891-905. doi: 10.1021/jm100488w.
Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99% of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1% of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone.
虚拟和高通量筛选 (HTS) 应该具有互补的优势和劣势，但很少有前瞻性和全面比较它们的研究。我们对 197861 种化合物进行了平行对接和 HTS 筛选，以寻找针对恰加斯病的硫醇蛋白酶靶点 cruzain 的可逆竞争性抑制剂。在研究过程中，99%的命中化合物被作为假阳性而淘汰，只得到了 146 种表现良好的竞争性配体。这些配体分为五种化学型：两种化学型根据对接排名库中得分在前 0.1%的情况进行了优先级排序，两种化学型根据 HTS 中的行为和聚类进行了优先级排序，还有一种化学型根据这两种方法都进行了优先级排序。确定抑制剂/cruzain 晶体结构并将高得分对接命中化合物与实验进行比较，阐明了对接假阴性和假阳性的起源。优先考虑既可以通过对接预测又可以在 HTS 中发挥活性的分子，可以得到表现良好的分子，相对不受两种技术各自容易出现的假阳性的干扰。
