How Size Matters: Diversity for Fragment Library Design

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Yun Shi, Mark von Itzstein

Abstract

Fragment-based drug discovery (FBDD) has become a major strategy to derive novel lead candidates for various therapeutic targets, as it promises efficient exploration of chemical space by employing fragment-sized (MW < 300) compounds. One of the first challenges in implementing a FBDD approach is the design of a fragment library, and more specifically, the choice of its size and individual members. A diverse set of fragments is required to maximize the chances of discovering novel hit compounds. However, the exact diversity of a certain collection of fragments remains underdefined, which hinders direct comparisons among different selections of fragments. Based on structural fingerprints, we herein introduced quantitative metrics for the structural diversity of fragment libraries. Structures of commercially available fragments were retrieved from the ZINC database, from which libraries with sizes ranging from 100 to 100,000 compounds were selected. The selected libraries were evaluated and compared quantitatively, resulting in interesting size-diversity relationships. Our results demonstrated that while library size does matter for its diversity, there exists an optimal size for structural diversity. It is also suggested that su...Continue Reading

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Citations

Nov 30, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Philine KirschMartin Empting
Jan 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Li Shi, Naixia Zhang
Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Abdul-Hamid EmwasMariusz Jaremko
Dec 9, 2020·Journal of Chemical Information and Modeling·Laura Chachulski, Björn Windshügel

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