Fragment-Based Approaches in Drug Discovery and Chemical Biology

Abstract

Fragment-based approaches to finding novel small molecules that bind to proteins are now firmly established in drug discovery and chemical biology. Initially developed primarily in a few centers in the biotech and pharma industry, this methodology has now been adopted widely in both the pharmaceutical industry and academia. After the initial success with kinase targets, the versatility of this approach has now expanded to a broad range of different protein classes. Herein we describe recent fragment-based approaches to a wide range of target types, including Hsp90, β-secretase, and allosteric sites in human immunodeficiency virus protease and fanesyl pyrophosphate synthase. The role of fragment-based approaches in an academic research environment is also examined with an emphasis on neglected diseases such as tuberculosis. The development of a fragment library, the fragment screening process, and the subsequent fragment hit elaboration will be discussed using examples from the literature.

Targeting Antibiotic Resistance

“…Once the structure of a target or a co‐crystal structure of a target together with a bound ligand is available, structure‐based design can be applied both rationally and creatively in order to tailor the properties of a drug molecule. Fragment‐based approaches are used for the identification of chemical starting points for lead optimization, virtual docking allows in silico screening, and de novo approaches generate new chemotypes for drug molecules 4, 5, 6, 7, 8…”

Overcoming the Limitations of Fragment Merging: Rescuing a Strained Merged Fragment Series Targeting Mycobacterium tuberculosis CYP121

“…At its heart, this powerful methodology involves the structure‐guided design and synthesis of potent ligands from weak binding low‐molecular‐weight fragment molecules (typically <250 Da) 1. There are three main strategies for the elaboration of initial fragment hits:1a 1) fragment growing, in which fragments are grown structurally into new unexplored regions within/around their binding site; 2) fragment linking, where two or more fragments that bind in close proximity within the binding pocket are covalently linked; and 3) fragment merging, in which the substructural components of fragments that overlap in the binding cavity are fused together. Although fragment merging represents a particularly elegant solution, the strategy remains relatively unexplored in fragment‐based ligand discovery (FBLD) campaigns 1.…”

“…Although fragment merging represents a particularly elegant solution, the strategy remains relatively unexplored in fragment‐based ligand discovery (FBLD) campaigns 1. Rather, hybrid merged molecules are far more common, formed by combining fragment hits with elements from a known larger substrate, cofactor, or inhibitor 1a. 2…”

Le criblage de fragments

“…Depuis, l'approche s'est généralisée à l'ensemble des sociétés pharmaceutiques, et se développe parallèlement dans le secteur académique [16,17]. Le premier médicament issu de cette approche FBBD a été accepté par la FDA (food and drug administration) en août 2011.…”