In the drug development process, optimization of properties and biological activities of small molecules is an important task to obtain drug candidates with optimal efficacy when first applied in subsequent clinical studies. However, despite its importance, large-scale investigations of the optimization process in early drug discovery are lacking, likely due to the absence of historical records of different chemical series used in past projects. Here, we report a retrospective reconstruction of ∼3000 chemical series from the Novartis compound database, which allows us to characterize the general properties of chemical series as well as the time evolution of structural properties, ADMET properties, and target activities. Our data-driven approach allows us to substantiate common MedChem knowledge. We find that size, fraction of sp³-hybridized carbon atoms (F_sp³), and the density of stereocenters tend to increase during optimization, while the aromaticity of the compounds decreases. On the ADMET side, solubility tends to increase and permeability decreases, while safety-related properties tend to improve. Importantly, while ligand efficiency decreases due to molecular growth over time, target activities and lipophilic efficiency tend to improve. This emphasizes the heavy-atom count and log D as important parameters to monitor, especially as we further show that the decrease in permeability can be explained with the increase in molecular size. We highlight overlaps, shortcomings, and differences of the computationally reconstructed chemical series compared to the series used in recent internal drug discovery projects and investigate the relation to historical projects.

中文翻译：

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诺华 25 年的小分子优化：化学系列演变的回顾性分析

在药物研发过程中，优化小分子的性质和生物活性是获得首次应用于后续临床研究时具有最佳疗效的候选药物的重要任务。然而，尽管它很重要，但缺乏对早期药物发现优化过程的大规模调查，这可能是由于缺乏过去项目中使用的不同化学系列的历史记录。在这里，我们报告了诺华化合物数据库中约 3000 个化学系列的回顾性重建，这使我们能够表征化学系列的一般特性以及结构特性、ADMET 特性和目标活动的时间演变。我们的数据驱动方法使我们能够证实常见的 MedChem 知识。我们发现 sp 的大小，分数^3-杂化碳原子（F _{sp ³}），在优化过程中立体中心的密度趋于增加，而化合物的芳香性降低。在 ADMET 方面，溶解度趋于增加，渗透性降低，而与安全相关的性能趋于改善。重要的是，虽然随着时间的推移分子生长会导致配体效率降低，但靶标活性和亲脂效率往往会提高。这强调了重原子计数和 log  D作为要监测的重要参数，特别是当我们进一步表明渗透率的降低可以用分子大小的增加来解释时。我们强调了与最近内部药物发现项目中使用的系列相比，计算重建的化学系列的重叠、缺点和差异，并调查了与历史项目的关系。