This project can be summarized as the detailed analysis of protein structures and bioactivity data for a better understanding of protein-ligand interactions towards selectivity and promiscuity of ligand binding. The analysis of ligand bioactivity data is based on the similar property principle, that similar molecules are likely to show similar properties, e.g., bioactivity.1  In general, molecular similarity is analysed regarding the complete molecular structure but similar scaffolds can also indicate similar ligand binding. The term ‘privileged structure’ was initially introduced by Evans et al. in 19882 and defined as a core structure that provides useful ligands for more than one receptor. In the context of this project, privileged and promiscuous scaffolds are defined as follows: Privileged scaffolds are core building blocks that can be found in many different ligands that interact with different proteins. These scaffolds are not interacting directly with the protein but must be decorated with different sidechains for creating the final ligand. In contrast, promiscuous scaffolds or fragments are common ligand moieties that directly bind to specific and reoccurring binding subpockets that can be found in different proteins. Therefore, they should be usable as starting points for fragment-based design. 

A detailed scaffold-based analysis of bioactivity data was the starting point for the identification of a bicyclic scaffold and a similar hydrophobic binding subpocket in different proteins.3 Two of the identified proteins, the bromodomain-containing protein 4 (BRD4) and the peroxisome-proliferator activated receptor gamma (PPARγ), show a high binding site similarity with an unexpected similar ligand-binding. This should allow the design of a polypharmacology-based ligand targeting both proteins. Other proteins also have this similar hydrophobic subpocket, but the rest of the binding site is completely different. Here, the hydrophobic subpocket can be addressed by the identified promiscuous scaffold or fragment allowing fragment-based molecular design approaches for the development of a new ligand for this specific protein target.

In future porjects, further promiscuous scaffolds and their specific binding environment in different proteins should be identified.  For this, scaffold-based analysis will be combined with binding site comparison.4 The identified scaffolds should be useful starting points for fragment-based molecular design of ligands for proteins that contain this specific binding environments (or subpockets). In addition, more insights into selectivity and promiscuity of ligand-binding for the development of polypharmacology-based ligands should be retrieved using these analyses.

References:

  1. Humbeck, L., Koch, O* What can we learn from bioactivity data? Cheminformatics tools and applications in chemical biology research, ACS Chem. Biol. 2017, 12, 23-35, Review. http://dx.doi.org/10.1021/acschembio.6b00706
  2. Evans, B. E., Rittle, K. E., Bock, M. G., DiPardo, R. M., Freidinger, R. M., Whitter, W. L., Lundell, G. F., Veber, D. F., Anderson, P. S., Chang, R. S. L., Lotti, V. J., Cerino, D. J., Chen, T. B., Kling, P. J., Kunkel, K. A., Springer, J. P., Hirshfield, J. Methods for drug discovery: Development of potent, selective, orally effective cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235–2246.
  3. Humbeck, L., Pretzel, J., Spitzer, S., Koch, O.* Discovery of an Unexpected Similarity in Ligand Binding Between BRD4 and PPARγ. ChemRxiv. 2019 https://doi.org/10.26434/chemrxiv.11472618
  4. Ehrt, C., Brinkjost, T., Koch, O.* A Benchmark Driven Guide to Binding Site Comparison: An Exhaustive Evaluation Using Tailor-Made Datasets, PLOS Comp. Bio. 2018, 14, e1006483. https://doi.org/10.1371/journal.pcbi.1006483