Binding of Ligands to GPCRs ? How Valid is a Thermodynamic Discrimination of Antagonists and Agonists?

Straßer, Andrea; Wittmann, Hans Joachim

doi:10.4172/2161-0398.s1-001

Cited by 1 publication

(1 citation statement)

References 33 publications

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“…Our analysis led to the conclusion that enthalpic barriers due to polar ligand desolvation in an unfavorable hydrophobic pocket greatly impact the association kinetics. A literature search for enthalpic (Δ H ⧧ on ) and entropic (− T Δ S ⧧ on ) contributions to the association barrier Δ G ⧧ on identified experimental data on various drugs and drug-like molecules for the drug targets MAP38α, thrombin, gpH3 receptor, HIV1 protease, and FGFR1 (see Table S1). Interestingly, in all those cases the enthalpic contribution to the association barrier was dominant.…”

Section: Resultsmentioning

confidence: 99%

Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors

et al. 2018

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Residence time and more recently the association rate constant k 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 of 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 of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant k decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward 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.

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