Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

How Size Matters: Diversity for Fragment Library Design

Version 1 : Received: 18 July 2019 / Approved: 19 July 2019 / Online: 19 July 2019 (07:54:41 CEST)

A peer-reviewed article of this Preprint also exists.

Shi, Y.; von Itzstein, M. How Size Matters: Diversity for Fragment Library Design. Molecules 2019, 24, 2838. Shi, Y.; von Itzstein, M. How Size Matters: Diversity for Fragment Library Design. Molecules 2019, 24, 2838.


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 maximise 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 such quantitative measures can guide the design of diverse fragment libraries under different circumstances.


diversity; fragment-based drug discovery; library design; library size


Chemistry and Materials Science, Medicinal Chemistry

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