How Size Matters: Diversity for Fragment Library Design

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Shi, Yun
von Itzstein, Mark
Griffith University Author(s)
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2019
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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 such quantitative measures can guide the design of diverse fragment libraries under different circumstances.

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Molecules

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24

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15

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© 2019 The Author(s). Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Biomedical and clinical sciences

Pharmacology and pharmaceutical sciences

Medicinal and biomolecular chemistry

Organic chemistry

Theoretical and computational chemistry

Science & Technology

Life Sciences & Biomedicine

Physical Sciences

Biochemistry & Molecular Biology

Chemistry, Multidisciplinary

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Shi, Y; von Itzstein, M, How Size Matters: Diversity for Fragment Library Design, Molecules, 2019, 24 (15)

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