Fragment-based Lead Preparation in Drug Discovery and Development

Fragment-based drug discovery (FBDD) is a powerful approach in drug design [1-4], which allows going beyond the conventional high-throughput screening (HTS). The fact of the matter is, small fragments bind to more sites of a target protein, thus producing a larger number of favorable interactions – hits. To identify the fragment hits, FBDD employs various screening methods based on advanced biophysical, biochemical, and bioinformatics techniques [1,2,5]. However, once the set of initial fragments is selected, a new challenge emerges: turning a fragment-based hit into a lead-like compound with further potential for drug development. At this stage, researchers aim at transforming the promising fragments into larger ligands with higher affinity and activity against the target. This hit-to-lead optimization can be realized via several strategies [1-3, 5-7]: fragment growing, merging, or linking (Fig. 1).

Figure 1. Fragment optimization approaches [5] with examples of application [7]: a) fragment growing, b) fragment merging, and c) fragment linking.

Fragment growing (Fig. 1a) is the most straightforward approach to getting a functional compound. Within this strategy, additional chemical groups are attached to the fragment-based hit to increase its molecular weight and enhance the potency of ligand-receptor interaction. Such a “smart building” of fragment-based compounds brings results: Fig. 2 [1, 8-11] shows the examples of approved drugs obtained by fragment growing.

Figure 2. Approved drugs obtained with FBDD (picture from [1]).

Fragment merging (also called scaffold hopping) is a practicable strategy when two fragments bind to overlapping regions of the same enzyme (Fig. 1b). In this case the structural similarity of the initial hits allows merging them into one compound with higher potency. The fragment concatenation occurs through the fusion of the overlapping parts; along with that, it is important to retain the binding properties of the initial fragments and their positions with respect to the target. The use of fragment merging for optimization may significantly increase the functionality of the resulting compound, as was achieved for several targets [12-13].

Fragment linking (Fig. 1c) aims to combine two or more fragments that bind to adjacent regions of a target protein. Compared to merging, linking is more challenging as it requires an extra component – a linker – that connects the selected fragments to provide optimal geometry and functionality of the resulting lead. The suitable linker should be a “puzzle detail” that keeps the favorable orientation of the initial fragments and has no negative effect on the compound activity. Despite the complexity of this strategy, it is a powerful way of fragment optimization and consequent drug design due to the striking increase of potency in case of success [1,3,7]. 

The hit-to-lead optimization can be performed using each of the strategies mentioned above, or their combination, and in parallel with other approaches such as HTS. In this way, the advanced methods of FBDD are boosting the complex process of finding and verifying the drug candidates.

To contribute to a successful development  of the FBDD programs, Life Chemicals has designed a variety of Fragment Libraries based on its proprietary Fragment-like Compound Collection (examples Fig.3). Our experienced R&D team can assist you in design and synthesis of compound libraries based on your hits and scaffolds, SAR exploration and hit-to-lead optimization. Read more about our custom synthesis services.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

Please, visit our Website for more information and download SD files with compound structures in the Downloads section. Custom compound selection based on specific parameters can be performed on request, with competitive pricing and the most convenient terms provided.

Figure 3. Representative fragment-like molecules with experimental solubility data from Life Chemicals Fragment Collection

References

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12. Li, Q., Meng, L., Zhou, S., et al. (2019). Rapid generation of novel benzoic acid–based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: scaffold-hopping and prodrug study. Eur. J. Med. Chem. 180, 509–523. doi: 10.1016/j.ejmech.2019.07.045
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