Charting the Space of Binding-Site Architectures in Proteins: A Large-Scale Analysis

• Applicant: Dr. Tina Ritschel
• Subject Area: Pharmacy
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 170851976

Drug discovery programs typically start with a high-throughput screen (HTS) for compounds exhibiting the desired biological activity. To maximize the number of hits, compound libraries screened by HTS are enriched with so-called privileged scaffolds, chemical substructures known to be present in ligands for multiple receptors. While the existence of privileged scaffolds is generally accepted, little is known about why these substructures are so special. This study aims to systematically analyze the ligand binding sites of protein receptors to reveal the relationship between privileged scaffolds and their binding sites. To identify the characteristics of receptors that make them preferably interact with privileged scaffolds, a large-scale analysis will be performed of all protein-ligand complexes deposited in the Protein Data Bank (PDB). To render this analysis computationally feasible a special binding-site representation, based on pharmacophore fingerprints, will be used. The resulting chart of naturally occurring binding sites in protein space, will allow for the extraction of privileged binding site characteristics, which in turn will lead to improved principles for screening compound library design.

• DFG Programme: Research Fellowships
• International Connection: Netherlands
• Host: Professor Dr. Jacob de Vlieg