Over recent decades there have been many improvements in the techniques available for predicting the pharmaceutically relevant properties of a compound. However, predicting the binding strength between a compound and a protein target remains an unsolved problem. This is important because the ability of a compound to cause a physiological effect (its efficacy) depends upon such binding in most cases. The challenge of predicting this binding strength has been complicated in recent years by the insights provided from the measurements of thermodynamics and kinetics. Those attempting to design drugs now have more parameters, rather than less to worry about! At John Moores University, we are undertaking a program of work to design and evaluate computational tools to predict the thermodynamics and kinetics of binding. These tools will help drug designers to navigate this complex array of interdependent properties. A first step has been to collect a number of new experimental data sets which will underpin model development. The requirements for these datasets are that they provide as full a set of thermodynamic and kinetic measurements for a panel of compounds binding to a particular protein as possible. Further, protein-ligand crystal structure data must be available. In this presentation, we will disclose the insights available for the first of these systems: PHGDH. A congeneric series of ligands has been studied using ITC and SPR and the observations rationalized with experimental structures and docking calculations. 1.Ladbury, J.E., Klebe, G. & Freire, E., 2010. Adding calorimetric data to decision making in lead discovery: a hot tip. Nature reviews. Drug discovery, 9(1), pp.23–27. 2.Tummino, P.J. & Copeland, R. a, 2008. Residence time of receptor-ligand complexes and its effect on biological function. Biochemistry, 47(20), pp.5481–92.

PHGDH: A case study for the structural rationalization of thermodynamics and kinetics of protein-ligand binding

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.