Paradoxically, most flexible ligand binds most entropy-favored: intriguing impact of ligand flexibility and solvation on drug–kinase binding

  • Biophysical parameters can accelerate drug development; e.g., rigid ligands may reduce entropic penalty and improve binding affinity. We studied systematically the impact of ligand rigidification on thermodynamics using a series of fasudil derivatives inhibiting protein kinase A by crystallography, isothermal titration calorimetry, nuclear magnetic resonance, and molecular dynamics simulations. The ligands varied in their internal degrees of freedom but conserve the number of heteroatoms. Counterintuitively, the most flexible ligand displays the entropically most favored binding. As experiment shows, this cannot be explained by higher residual flexibility of ligand, protein, or formed complex nor by a deviating or increased release of water molecules upon complex formation. NMR and crystal structures show no differences in flexibility and water release, although strong ligand-induced adaptations are observed. Instead, the flexible ligand entraps more efficiently water molecules in solution prior to protein binding, and by release of these waters, the favored entropic binding is observed.

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Author:Barbara Wienen-SchmidtORCiD, Hendrik R. A. JonkerORCiD, Tobias Wulsdorf, Hans-Dieter Gerber, Krishna SaxenaORCiDGND, Denis KudlinzkiGND, Sridhar SreeramuluORCiDGND, Giacomo Parigi, Claudio Luchinat, Andreas Heine, Harald SchwalbeORCiDGND, Gerhard KlebeORCiDGND
Pubmed Id:
Parent Title (English):Postprint, zuerst in: Journal of Medicinal Chemistry
Document Type:Article
Year of Completion:2019
Date of first Publication:2018/06/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/09/25
Page Number:12
First Page:5922
Last Page:5933
Postprint, zuerst in: Journal of Medicinal Chemistry  61.2018, 14, S. 5922-5933, doi: 10.1021/acs.jmedchem.8b00105
Gefördert durch: European Union: Horizon 2020. Infrastructure for NMR, EM and X-rays for Translational Research, iNEXT, H2020 Grant # 653706
Institutes:Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoDeutsches Urheberrecht