Ligand Desolvation steers on-rate and impacts Drug Residence Time of Heat shock protein 90 (Hsp90) Inhibitors

Author(s)
Doris Alexandra Schuetz, Lars Richter, Marta Amaral, Melanie Grandits, Ulrich Graedler, Djordje Musil, Hans-Peter Buchstaller, Hans-Michael Eggenweiler, Matthias Frech, Gerhard F Ecker
Abstract

Residence time - and more recently - the association rate constant kon are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, Structure-Kinetic relationships, X-ray crystallography and Molecular Dynamics simulations were combined to retrieve a concrete scheme how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant kon decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand, which point towards a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13- and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.

Organisation(s)
Department of Pharmaceutical Chemistry
External organisation(s)
Merck KGaA, iBET - Instituto de Biologia Experimental e Tecnológica
Journal
Journal of Medicinal Chemistry
Volume
61
Pages
4397–4411
ISSN
0022-2623
DOI
https://doi.org/10.1021/acs.jmedchem.8b00080
Publication date
2018
Peer reviewed
Yes
Austrian Fields of Science 2012
Structural biology
Portal url
https://ucris.univie.ac.at/portal/en/publications/ligand-desolvation-steers-onrate-and-impacts-drug-residence-time-of-heat-shock-protein-90-hsp90-inhibitors(7165d8cb-8fc0-4718-8778-c9378fb6c4ab).html