A decade ago target residence time was reconsidered as a parameter to increase the therapeutic index of drug molecules. An idea driven by Copeland, Swinney and others. They suggested that the key determinant of in vivo pharmacological activity is not only the binding affinity of a drug for its target but the lifetime, or residence time. The model for that concept seems simple: the pharmacological activity depends on the binding of the drug to its target, and pharmacological activity will usually persist while the drug remains bound. Having in mind that a biological relevant drug target interaction kinetic is a parameter which could be used to develop improved drugs in terms of efficacy, side effects and even selectivity, the Innovative Medicines Inititiave supported a European consortium to work on that topic. Pharma companies and academic institution work jointly on kinetics for Drug Discovery. Hsp90 is one of the projects beside many others. As a key protein involved in a variety of pathways including cell signaling, proliferation and survival, protein folding and tumor repression. Many proteins in tumor cells are dependent upon the Hsp90 protein folding machinery for their stability, refolding and maturation and therefore it has emerged as a as a promising target for the treatment of cancer. During our internal project, we observed a correlation between target occupancy, inhibitor residence time and cellular efficacy in a cell based assay. In that sense the amino-terminal ATP-binding domain has been used as a model system to study the mechanism of interaction by different biophysical, structural and MD methods. A detailed structure-kinetic relationship study of HSP90 with resorcinol compounds revealed that variations of resorcinol substituents can cause the compounds to change from fast to slow binding kinetics to elongated residence times of more than two orders of magnitude. Transition state thermodynamic analysis by SPR in combination with 3D structural information provide first hypothesis on the energetic origins determining association/dissociation processes. The dynamics of the ligand and the protein in the solvent need to be accounted for to get a better understanding of the molecular mechanism and kinetics of inhibitor interaction with the target protein.

Drug target residence time in the early drug discovery phase: HSP90, a model to gain insight into the molecular mechanism of kinetics

253rd National Meeting (2017)

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