Concepts and Core Principles of Fragment-Based Drug Design

Abstract

In this review, a general introduction to fragment-based drug design and the underlying concepts is given. General considerations and methodologies ranging from library selection/construction over biophysical screening and evaluation methods to in-depth hit qualification and subsequent optimization strategies are discussed. These principles can be generally applied to most classes of drug targets. The examples given for fragment growing, merging, and linking strategies at the end of the review are set in the fields of enzyme-inhibitor design and macromolecule-macromolecule interaction inhibition. Building upon the foundation of fragment-based drug discovery (FBDD) and its methodologies, we also highlight a few new trends in FBDD.

Keywords: biophysical screening; fragment optimization; fragment-based drug design; ligand efficiency; rule-of-three.

Figure 1

Schematic depiction illustrating the SPR-based competition experiment. (Left) The docking mode of inhibitor 1 bound to the target enzyme PqsD and the active site cysteine (Cys112) are indicated. (Right) SPR sensorgrams with (blue) and without (red) covalent active-site blockade via substrate preconditioning (RU = SPR response units) are given. The lack of SPR response (blue) indicates that inhibitor 1 is binding at the active site [114].

Figure 2

Fragment screening cascade using: SPR and DSF selection steps, followed by functional evaluation via fluorescence polarization, which resulted in three fragment hits. Growth vector identification through initial analoging allowed for growing of fragment 2 into a double-digit micromolar validated hit.

Figure 3

An example of a compound merging attempt. Fragment 1 and compound 6 were merged, guided by an SPR-informed docking poses, yielding inhibitor 7. If X-ray structures for the individual inhibitors were available, this attempt could be improved by adjusting the merging modality [129]. Light blue: carbon atoms of inhibitor 1 and carbons resembling an overlapping motif in inhibitor 6. Light green: the other carbon atoms of inhibitor 6. Blue: nitrogen. Red: oxygen. Hydrogen omitted for clarity.

Figure 4

Structures of hits 8 and 9 and linked bisacylhydrazone linked inhibitors 10 and 11 [131].

Figure 5

Schematic representation of target-directed dynamic combinatorial chemistry.