Skaggs Doctoral Program in the Chemical and Biological Sciences, Scripps Research, La Jolla, California 92037, United States.
Department of Pharmaceutical Sciences, University of California, Irvine, California 92697, United States.
J Chem Inf Model. 2024 Jun 24;64(12):4661-4672. doi: 10.1021/acs.jcim.4c00232. Epub 2024 Jun 11.
DNA-encoded library technology grants access to nearly infinite opportunities to explore the chemical structure space for drug discovery. Successful navigation depends on the design and synthesis of libraries with appropriate physicochemical properties (PCPs) and structural diversity while aligning with practical considerations. To this end, we analyze combinatorial library design constraints including the number of chemistry cycles, bond construction strategies, and building block (BB) class selection in pursuit of ideal library designs. We compare two-cycle library designs (amino acid + carboxylic acid, primary amine + carboxylic acid) in the context of PCPs and chemical space coverage, given different BB selection strategies and constraints. We find that broad availability of amines and acids is essential for enabling the widest exploration of chemical space. Surprisingly, cost is not a driving factor, and virtually, the same chemical space can be explored with "budget" BBs.
DNA 编码文库技术为药物发现探索化学结构空间提供了近乎无限的机会。成功的导航取决于文库的设计和合成，这些文库具有适当的物理化学性质 (PCPs) 和结构多样性，同时符合实际考虑因素。为此，我们分析了组合文库设计的约束条件，包括化学循环的数量、键构建策略和砌块 (BB) 类别的选择，以追求理想的文库设计。我们比较了两种循环文库设计（氨基酸+羧酸、伯胺+羧酸）在 PCPs 和化学空间覆盖方面的情况，考虑了不同的 BB 选择策略和约束条件。我们发现，广泛的胺和酸的可用性对于实现化学空间的最广泛探索是至关重要的。令人惊讶的是，成本不是一个驱动因素，实际上，使用“预算”砌块可以探索相同的化学空间。
