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Seminar by Dr.Daria Kokh

HITS, Heidelberg (Germany)

05 May 2017 11:00
05 May 2017 12:00
Lecture room 2009, Jülich GRS building (16.15)

Kinetics of drug-protein binding have a crucial influence on drug efficacy and safety. However, because of the high cost and low throughput of available experimental techniques, the kinetic characteristics of lead compounds are often considered only in the latter stages of drug discovery. This implies a reduction in the chemical space available for kinetic optimization. In my talk, I will present results of a detailed experimental and computational study of both the kinetics and thermodynamics of small molecules binding to a drug target, human heat shock protein 90 (HSP90). This study showed an unusual binding mechanism of slow dissociation and high affinity drug-like molecules to the N-terminal domain of HSP90, which is found to be mainly entropically driven by the conformational flexibility of the protein in the ligand-bound state. To assist the rational design of compounds with desired dissociation rates, we have developed a procedure based on the random acceleration molecular dynamics (RAMD) [1]0 simulation method. This method provides an estimate of relative dissociation rate constants and gives insights into ligand unbinding pathways. In the second part of my talk I’ll demonstrate an evaluation of this method on over 50 diverse inhibitors of HSP90 and on about 10 inhibitors (both type I and type II) of a kinase protein.

This work was supported by the EU/EFPIA Innovative Medicines Initiative (IMI) Joint Undertaking, K4DD (grant no. 115366) and by the Klaus Tschira Foundation. We acknowledge PRACE for awarding us access to resource Marconi based in Italy at Cineca.

[1] Lüdemann, S. K.; Lounnas, V.; Wade, R. C. J. Mol. Biol. 2000, 303 (5), 797–811.