Charting the Space of Binding-Site Architectures in Proteins: A Large-Scale Analysis
Zusammenfassung der Projektergebnisse
The focus of this research project was the analysis of protein binding sites on a large scale. Protein binding sites are the main location of action for drug molecules; therefore a thorough understanding of where and why drug molecules are binding is useful for the development of drug molecules. In the first phase of the project a method was developed which allows fast protein binding site comparison. This resulted in the pharmacophore fingerprint method KRIPO. The identification of similar binding sites both within and across protein families was a major focus. Only by being able to find similarities beyond protein families will result in new valuable insides in protein binding site similarities. Having the method in place I studied systematically the ligand binding sites of protein receptors to reveal the relationship between privileged scaffolds and their binding sites. For this BIG DATA analysis collaborations with The Netherlands eScience Center (Amsterdam, NL) and the group of Prof. Buydens for Chemometics (Radboud University Nijmegen, NL) are on-going. An additional application of KRIPO is the detection of polypharmacological effects. “The most fruitful basis for the discovery of a new drug is to start with an old one” is a citation from Sir James Black’s Nobel laureate (1988). The background of this statement lies in the fact that most drugs are able to bind to multiple protein targets in the human body, known as polypharmacology. This behaviour can lead to unwanted side effects, and innovative research to avoid such adverse properties is of great importance. Fortunately, polypharmacology can also be used to create new therapeutic approaches, since the protein to which a drug binds causing a side effect in one case, can be the main target for another treatment. Many cases report about the problems and opportunities of polypharmacology. In order for a drug to bind to multiple targets, the interaction sites of these targets must be similar on a molecular level. KRIPO was used to unravel the molecular mechanisms of adverse drug effects of HMG-CoA reductase inhibitors, better known as statins. The development of the KRIPO and its application to pharmaceutical and medicinal chemistry questions was successfully achieved in this project and novel findings in the field of drug-side effects were made.
Projektbezogene Publikationen (Auswahl)
- Pharmacophore fingerprintbased approach to binding site subpocket similarity and its application to bioisostere replacement. J. Chem. Inf. Model, 2012, 52, 2031-2043
Wood, D.; de Vlieg, J.; Wagener, M.; Ritschel, T.
