K4DD research published in Nature Communications


A considerable number of approved drugs show non-equilibrium binding characteristics, emphasizing the potential role of drug residence times for in vivo efficacy. Therefore, a detailed understanding of the kinetics of association and dissociation of a target–ligand complex might provide crucial insight into the molecular mechanism-of-action of a compound. With this goal in mind, Kinetics for Drug Discovery (K4DD-https://db.k4dd.eu) consortium was initiated to explore these concepts and ultimately to improve decision making in drug discovery, thus leading to a better selection of interesting compounds to be profiled further.

The work from K4DD partners iBET, Merck KGaA, Heidelberg Institute for Theoretical Studies and ITQB NOVA has resulted in a publication in the high-impact journal Nature Communications. The comprehensive study gives insights into the contribution of protein dynamics into the binding and unbinding mechanism of small drug-like molecules to human Hsp90 by combining thermodynamics and kinetics studies as well as molecular dynamics simulations.

Comparison of different conformations of N-HSP90 binding site

Reference: Amaral M, Kokh D, Wegener A, Bomke J, Buchstaller HP, Eggenweiler HM, Matias P, Wade RC, Frech M. (2017) “Protein conformational flexibility modulates kinetics and thermodynamics of drug binding” Nature Comms. Doi: 10.1038/s41467-017-02258-w