3D Molecular Descriptors Important for Clinical Success

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.临床候选药物的药代动力学与安全性特征，在很大程度上受其必需的理化性质影响。尤为关键的是，已有研究证实，二维分子描述符（2D molecular descriptors）——如sp3碳原子占比（Fraction of Sp3 carbon atoms，简称Fsp3）与手性中心数目——与药物临床研发成功率存在相关性。本研究通过分析烟碱类配体的蛋白质组学脱靶命中速率，发现基于形状的三维分子描述符（如回转半径与影子指数）在区分配体脱靶泛性方面，表现优于Fsp3与手性中心数目。我们已推导得出配体具备低脱靶泛性所需的关键描述符阈值。我们以MDL药物数据报告库（MDL Drug Data Report，简称MDDR）为研究数据集，追踪化合物从临床前阶段向上市阶段的研发全流程，结果显示：相较于Fsp3与正辛醇-水分配系数对数（LogD），上述基于形状的三维分子描述符，能更精准地预测处于临床前及Ⅰ期阶段的化合物相较于退市药物的临床研发成功率。此外，这些计算得到的三维分子描述符，与实验测得的溶解度——已知的影响临床研发成功的核心理化性质之一——呈现显著相关性。我们还发现，约84%的已上市药物满足影子指数或Fsp3判定标准，而退市及终止研发的化合物则未达到该标准。本研究表明，芳香环数目较少的球形化合物（而非长条形类似物），从临床试验推进至上市的概率更高。