Medicinal chemists receive ECHO grant to study binding kinetics and thermodynamics

Prof. dr. Iwan de Esch and Dr. Maikel Wijtmans of the Division of Medicinal Chemistry have been awarded an ECHO grant by the Netherlands Organization for Scientific Research (NWO) of €260.000. The grant enables them to further study molecular interactions between proteins and ligands and strengthen their fragment-based drug design approach for the development of new drug molecules.

05/15/2014 | 2:16 PM

Fragment-based drug design (FBDD) is a highly efficient approach to develop drug molecules. When a protein is found to associated to a disease, and structural protein information, biochemical and biophysical assays indicate a drug target candidacy, FBDD can be employed. First, small fragments that bind to different parts of the protein are identified and subsequently grown and combined into bigger and more potent ligands.

Throughout these studies, the relationship between the new molecule’s 3D structure and its biological activity can be determined via the structure-activity relationship studies. Lately, evidence is emerging that the use of the standard equilibrium dissociation constant – a measure for the ligand’s affinity to the target protein – to describe structure-activity relationships has limitations.

Better understanding of molecular interaction
Within their successful FBDD research line, De Esch and Wijtmans have found several examples where individual ligands display identical equilibrium dissociation constants for proteins within one family, but still favor binding to some of these proteins by showing  kinetic or thermodynamic selectivity. Thus far, these differences in binding to homologous proteins cannot efficiently be exploited in the drug development process, as there is limited understanding of the molecular features governing these binding properties.

The granted NWO ECHO project is entitled Breaking the equilibrium dissociation constant into fragments: the systematic use of binding kinetics and thermodynamics in FBDD approaches and will focus on the integral use of binding kinetics and thermodynamics in the FBDD process. This research will lead to better understanding of molecular interactions, hence making FBDD more efficient. This will be exemplified by the development  of drug molecules against African sleeping sickness, a grossly neglected parasitic disease.

Iwan de Esch   Maikel Wijtmans

Prof. dr. Iwan de Esch (l) and Dr. Maikel Wijtmans of the Division of Medicinal Chemistry receive an ECHO grant from NWO to implement binding kinetics and thermodynamics in their fragment-based drug design approach.

The ECHO grants programme facilitates curiosity-driven research by excellent researchers in chemistry. This allows creative, risky ideas to be pursued. These may be the seeds for future research themes and thus scientific innovation.  

More information
Division of Medicinal Chemistry

Key publication 1: Fragment growing induces conformational changes in acetylcholine-binding protein: a structural and thermodynamic analysis.

Key publication 2: Ligand based design of novel histamine Hreceptor antagonists; fragment optimization and analysis of binding kinetics.