Elucidating selectivity determining features of proteins with conserved binding sites

• Applicant: Professorin Dr. Tanja Schirmeister, since 7/2016
• Subject Area: Pharmacy ; Biochemistry
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252061573

Deriving selective inhibitors is a key objective in drug discovery. It has been demonstrated that this goal can be achieved even when the binding sites of a target and its anti-target(s) are conserved. However, it is currently not possible to do this in a rational manner because it is not understood what the driving forces for selective inhibition in these cases are. The proposed research addresses this unexplored area of molecular recognition. Over the last years it has become increasingly evident that the change in protein dynamics makes an important contribution to ligand binding energy. Therefore, our hypothesis is the following: One reason for selective inhibition is that the dynamics of related proteins changes to a different extent upon binding different ligands. As a consequence, the change in conformational entropy of these proteins is different and hence the difference in the binding energies of the ligands. Through our previous work we have access to a plethora of potent selective and non-selective N-myristoyltransferase (NMT) inhibitors and established crystallisation conditions and assay systems. This puts us in the unique position to probe this hypothesis using NMT as a model system by combining biophysical, computational and molecular biology methods

• DFG Programme: Research Grants
• Ehemalige Antragstellerin: Professorin Dr. Ruth Brenk, until 6/2016