It is far more difficult to design a small molecule that binds to the surface of a protein than one that fits inside (eg in an enzyme cavity). However, there are two excellent reasons to learn how to create surface-binding small molecules.
Small Molecules To Perturb Protein-protein Interactions. Intracellular signaling and extracellular recognition/adhesion processes both rely on carefully controlled protein-protein interactions. Many diseases are characterized by an imbalance in protein expression and interactions, and appropriately designed small molecules may be used to probe these interactions or perturb them.
Small Molecules To Bind Particular Cell Types. In oncology, for instance, diagnosis, imaging, and treatment are the cornerstones of medical care. Small molecules that selectively recognize proteins over-expressed on cancer cell surfaces can advance all these areas.
For these reasons, effective design of small molecules to bind protein surfaces is a huge challenge in contemporary organic chemistry.
Targeted PDT Agent Eradicates TrkC Expressing Tumors Via Photodynamic Therapy (PDT), C. S. Kue, A. Kamkaew, H. B. Lee, L. Y. Chung, L. V. Kiew, K. Burgess, Mol. Pharmaceutics, 2015, 12, 212-22.
Aza-BODIPY Dyes With Enhanced Hydrophilicity, A. Kamkaew, K. Burgess, Chem. Comm., 2015, 51, 10664-7.
Small Molecule Probes that Perturb A Protein-protein Interface In Antithrombin, D. Xin, A. Holzenburg, K. Burgess, Chem. Sci., 2014, 5, 4914-4921. DOI: 10.1039/c4sc01295j.
A Multi-faced Secondary Structure Mimics Based on Piperidine-Piperidinones, D. Xin, L. M. Perez, T. R. Ioerger, K. Burgess, Angew. Chem., Int. Ed., 2014, 53, 3594-3498. DOI: 10.1002/anie.201400927.
Exploring Key Orientations at Protein-Protein Interfaces with Small Molecule Probes, E. Ko, A. Raghuraman, L. M. Perez, T. R. Ioerger, K. Burgess, J. Am. Chem. Soc., 2013, 135, 167-173. DOI 10.1021/ja3067258.
(chosen from over 300).