Balancing Molecular Size, Activity, Permeability, and Other Properties: Drug Candidates in the Context of Their Chemical Structure Optimization,Journal of Chemical Information and Modeling

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Balancing Molecular Size, Activity, Permeability, and Other Properties: Drug Candidates in the Context of Their Chemical Structure Optimization
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-13 , DOI: 10.1021/acs.jcim.4c00898
Maximilian Beckers ₁ , Finton Sirockin ₁ , Nikolas Fechner ₁ , Nikolaus Stiefl ₁

Affiliation

Chemical structure optimization is a vital part of early drug discovery projects. Starting with compounds that show activity on the target of interest, the chemical structures are subsequently optimized toward a development candidate (DC) molecule with the best chances of clinical success. However, the DCs in the context of such optimization programs, as well as detailed characterization of major limiting factors, have not been investigated in detail so far. Here, we report an analysis of the historical DC molecules at Novartis since 2005 in the context of their optimization projects. Mapping the DCs into their respective chemical optimization series, we find that these tend to be synthesized rather early in a substantial number of cases. Further analysis of structural properties, ADMET, and potency-related readouts revealed that DC compounds tend to be generally significantly smaller, more permeable, and have higher ligand efficiency than other compounds sent to in vivo PK studies, which we also show for compounds from the same chemical series. Although this might seem obvious to most practitioners in medicinal chemistry, for all of these properties, we could show that they tend to evolve in an undesired direction during structure optimization. This highlights the difficulty of successfully translating our knowledge to medicinal chemistry optimizations.

中文翻译：

平衡分子大小、活性、渗透性和其他特性：候选药物化学结构优化

化学结构优化是早期药物发现项目的重要组成部分。从对感兴趣的靶标表现出活性的化合物开始，随后对化学结构进行优化，以获得最有可能获得临床成功的开发候选 (DC) 分子。然而，迄今为止，尚未对此类优化程序中的 DC 以及主要限制因素的详细特征进行详细研究。在此，我们报告了诺华公司自 2005 年以来在其优化项目中对历史 DC 分子的分析。将 DC 映射到各自的化学优化系列中，我们发现在很多情况下它们往往是很早就合成的。对结构特性、ADMET 和效价相关读数的进一步分析表明，与进行体内PK 研究的其他化合物相比，DC 化合物通常更小、渗透性更强，并且具有更高的配体效率，我们还对来自相同的化学系列。尽管这对于大多数药物化学从业者来说似乎是显而易见的，但对于所有这些特性，我们可以证明它们在结构优化过程中往往会朝着不希望的方向发展。这凸显了将我们的知识成功转化为药物化学优化的难度。

更新日期：2024-08-13

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