Building Block-Centric Approach to DNA-Encoded Library Design

被引:0
|
作者
Fitzgerald, Patrick R. [1 ]
Dixit, Anjali [2 ]
Zhang, Chris [3 ]
Mobley, David L. [2 ,3 ]
Paegel, Brian M. [2 ,3 ]
机构
[1] Scripps Res, Skaggs Doctoral Program Chem & Biol Sci, La Jolla, CA 92037 USA
[2] Univ Calif Irvine, Dept Pharmaceut Sci, Irvine, CA 92697 USA
[3] Univ Calif Irvine, Dept Chem, Irvine, CA 92697 USA
基金
美国国家卫生研究院;
关键词
HIGHLY POTENT; DRUG DISCOVERY; CHEMICAL SPACE; OPTIMIZATION; RECEPTOR; TECHNOLOGY; INHIBITORS; DIVERSE; COMPLEX;
D O I
10.1021/acs.jcim.4c00232
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:4661 / 4672
页数:12
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