Liu Fangyu, Mailhot Olivier, Glenn Isabella S, Vigneron Seth F, Bassim Violla, Xu Xinyu, Fonseca-Valencia Karla, Smith Matthew S, Radchenko Dmytro S, Fraser James S, Moroz Yurii S, Irwin John J, Shoichet Brian K
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Nat Chem Biol. 2025 Jan 3. doi: 10.1038/s41589-024-01797-w.
Virtual ligand libraries for ligand discovery have recently increased 10,000-fold. Whether this has improved hit rates and potencies has not been directly tested. Meanwhile, typically only dozens of docking hits are assayed, clouding hit-rate interpretation. Here we docked a 1.7 billion-molecule virtual library against β-lactamase, testing 1,521 new molecules and comparing the results to a 99 million-molecule screen where 44 molecules were tested. In a larger screen, hit rates improved twofold, more scaffolds were discovered and potency improved. Fifty-fold more inhibitors were found, supporting the idea that the large libraries harbor many more ligands than are being tested. In sampling smaller sets from the 1,521, hit rates only converged when several hundred molecules were tested. Hit rates and affinities improved steadily with docking score. It may be that as the scale of docking libraries and their testing grows, both ligands and our ability to rank them will improve.
用于配体发现的虚拟配体库最近增加到了原来的10000倍。这是否提高了命中率和效力尚未得到直接验证。与此同时，通常只对几十种对接命中物进行检测，这使得命中率的解读变得模糊。在此，我们针对β-内酰胺酶对接了一个包含17亿个分子的虚拟库，测试了1521个新分子，并将结果与一个包含9900万个分子的筛选结果进行比较，后者测试了44个分子。在更大规模的筛选中，命中率提高了两倍，发现了更多的支架结构，效力也有所提高。发现的抑制剂数量增加了50倍，这支持了这样一种观点，即大型库中含有的配体比正在测试的要多得多。从1521个分子中抽取较小的样本集时，只有在测试了几百个分子后，命中率才会趋于一致。命中率和亲和力随着对接分数的提高而稳步提升。随着对接库规模及其测试规模的扩大，配体以及我们对它们进行排序的能力可能都会得到提升。
