Protein-protein interactions have been implied in several diseases; and as a drug target, several efforts have been directed at designing potent drugs to modulate this interaction1. However, due to the large and plastic surface of PPIs, traditional drug discovery methods such as high throughput screening have been ineffective in developing potent lead drug candidates2. Unlike active site drug discovery, protein-protein interactions (PPI) lacks well defined binding regions. This makes fragment based drug design (FBDD) an effective alternative for designing inhibitors of PPIs3.
FBDD starts with the identification very small molecules (low molecular weight fragments) that can perturb the supposed 'hot spots' of PPIs of interest4. These fragments, generally, exhibit weak affinity for the PPI. Novel leads are then designed from the 'hit' fragments via fragment growth, combination or merging.
This presentation seeks to explore how fragment based drug discovery strategies are used to design novel potent small molecule inhibitors of PPIs. The design of non-peptide small molecule inhibitors of the Bcl-2 family of proteins is used as a case study.   

Selected References

1.    Feng, Y., Wang, Q. and Wang, T. (2017). Drug Target Protein-Protein Interaction Networks: A Systematic Perspective. BioMed Research International, pp.1-13.
2.    Milroy, L., Grossmann, T., Hennig, S., Brunsveld, L. and Ottmann, C. (2014). Modulators of Protein–Protein Interactions. Chemical Reviews, 114(9), pp.4695-4748.
3.    Hall, D., Kozakov, D., Whitty, A. and Vajda, S. (2015). Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery. Trends in Pharmacological Sciences, 36(11), pp.724-736.
4.    Park, H., Shin, Y., Kim, J. and Hong, S. (2016). Application of Fragment-Based de Novo Design to the Discovery of Selective Picomolar Inhibitors of Glycogen Synthase Kinase-3 Beta. Journal of Medicinal Chemistry, 59(19), pp.9018-9034.
5.    Zhou, H., Chen, J., Meagher, J., Yang, C., Aguilar, A., Liu, L., Bai, L., Cong, X., Cai, Q., Fang, X., Stuckey, J. and Wang, S. (2012). Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold. Journal of Medicinal Chemistry, 55(10), pp.4664-4682.
6.    Zhou, H.; Chen, J.; Meagher, J. L.; Yang, C.-Y.; Aguilar, A.; Liu, L.; Bai, L.; Cong, X.; Cai, Q.; Fang, X.; Stuckey, J. A.; Wang, S. (2012) Journal of Medicinal Chemistry, 55 (10), 4664–4682.