Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

TLDR

Fragment‑based drug discovery (FBDD) enables discovery of drug leads and chemical probes across broad chemical space, yet its systematic use in academia lags behind industry due to evolving design principles and a lack of up‑to‑date guidance. The perspective aims to examine the theoretical, practical, and strategic aspects of FBDD programs. It outlines guidelines for fragment library design, including optimal size, complexity, physicochemical and shape profiles, and best practices for compound storage, evaluation, and screening technologies. The authors compile industry experience to provide guidance that may benefit academic FBDD efforts.

Abstract

Fragment-based drug discovery (FBDD) is well suited for discovering both drug leads and chemical probes of protein function; it can cover broad swaths of chemical space and allows the use of creative chemistry. FBDD is widely implemented for lead discovery in industry but is sometimes used less systematically in academia. Design principles and implementation approaches for fragment libraries are continually evolving, and the lack of up-to-date guidance may prevent more effective application of FBDD in academia. This Perspective explores many of the theoretical, practical, and strategic considerations that occur within FBDD programs, including the optimal size, complexity, physicochemical profile, and shape profile of fragments in FBDD libraries, as well as compound storage, evaluation, and screening technologies. This compilation of industry experience in FBDD will hopefully be useful for those pursuing FBDD in academia.