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Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.

Original publication

DOI

10.1021/acs.jmedchem.1c01108

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

13/12/2021

Volume

64

Pages

17887 - 17900

Addresses

Departament de Farmacia i Tecnología Farmacèutica, i Fisicoquímica, Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.