Agarwal Rupesh, T Rajitha Rajeshwar, Smith Jeremy C
UT/ORNL Center for Molecular Biophysics, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831-6309, United States.
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996-1939, United States.
J Chem Inf Model. 2023 Dec 11;63(23):7444-7452. doi: 10.1021/acs.jcim.3c01533. Epub 2023 Nov 16.
Structure-based virtual high-throughput screening is used in early-stage drug discovery. Over the years, docking protocols and scoring functions for protein-ligand complexes have evolved to improve the accuracy in the computation of binding strengths and poses. In the past decade, RNA has also emerged as a target class for new small-molecule drugs. However, most ligand docking programs have been validated and tested for proteins and not RNA. Here, we test the docking power (pose prediction accuracy) of three state-of-the-art docking protocols on 173 RNA-small molecule crystal structures. The programs are AutoDock4 (AD4) and AutoDock Vina (Vina), which were designed for protein targets, and rDock, which was designed for both protein and nucleic acid targets. AD4 performed relatively poorly. For RNA targets for which a crystal structure of a bound ligand used to limit the docking search space is available and for which the goal is to identify new molecules for the same pocket, rDock performs slightly better than Vina, with success rates of 48% and 63%, respectively. However, in the more common type of early-stage drug discovery setting, in which no structure of a ligand-target complex is known and for which a larger search space is defined, rDock performed similarly to Vina, with a low success rate of ∼27%. Vina was found to have bias for ligands with certain physicochemical properties, whereas rDock performs similarly for all ligand properties. Thus, for projects where no ligand-protein structure already exists, Vina and rDock are both applicable. However, the relatively poor performance of all methods relative to protein-target docking illustrates a need for further methods refinement.
基于结构的虚拟高通量筛选用于早期药物发现。多年来,蛋白质-配体复合物的对接协议和评分函数不断发展,以提高结合强度和构象计算的准确性。在过去十年中,RNA也已成为新型小分子药物的一个靶标类别。然而,大多数配体对接程序已针对蛋白质而非RNA进行了验证和测试。在此,我们在173个RNA-小分子晶体结构上测试了三种最先进对接协议的对接能力(构象预测准确性)。这些程序分别是为蛋白质靶标设计的AutoDock4(AD4)和AutoDock Vina(Vina),以及为蛋白质和核酸靶标设计的rDock。AD4的表现相对较差。对于有结合配体晶体结构可用于限制对接搜索空间且目标是识别同一口袋新分子的RNA靶标,rDock的表现略优于Vina,成功率分别为48%和63%。然而,在更常见的早期药物发现场景中,即未知配体-靶标复合物结构且定义了更大搜索空间的情况下,rDock的表现与Vina类似,成功率较低,约为27%。发现Vina对具有某些物理化学性质的配体存在偏差,而rDock对所有配体性质的表现类似。因此,对于尚无配体-蛋白质结构的项目,Vina和rDock都适用。然而,相对于蛋白质靶标对接,所有方法的表现都相对较差,这表明需要进一步改进方法。