TY  - JOUR
A1  - Wienen-Schmidt, Barbara
A1  - Jonker, Hendrik R. A.
A1  - Wulsdorf, Tobias
A1  - Gerber, Hans-Dieter
A1  - Saxena, Krishna
A1  - Kudlinzki, Denis
A1  - Sreeramulu, Sridhar
A1  - Parigi, Giacomo
A1  - Luchinat, Claudio
A1  - Heine, Andreas
A1  - Schwalbe, Harald
A1  - Klebe, Gerhard
T1  - Paradoxically, most flexible ligand binds most entropy-favored: intriguing impact of ligand flexibility and solvation on drug–kinase binding
T2  - Postprint, zuerst in: Journal of Medicinal Chemistry
N2  - 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.
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51313
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-513139
N1  - 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
VL  - 61
IS  - 14
SP  - 5922
EP  - 5933
ER  -