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Kinetic and thermodynamic assessment of binding of serotonin transporter (SERT) inhibitors
Author(s) -
Martin Renee,
Henningsen R,
Suen A,
Stockdale D,
Apparsundaram S,
Milla M E
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.254.3
Subject(s) - chemistry , binding site , serotonin plasma membrane transport proteins , binding energy , entropy (arrow of time) , serotonin transporter , thermodynamics , gibbs free energy , stereochemistry , serotonin , biochemistry , receptor , physics , nuclear physics
Considering their shared mechanism of action, there is surprising diversity in the clinical outcomes of SERT inhibitors. Such behavior may arise from the binding modes of those inhibitors with SERT. We report here on the thermodynamics of ligand‐SERT interactions determined from equilibrium and kinetic binding analyses. All drugs excepting fluvoxamine displayed remarkably similar binding thermodynamics with relatively equal contributions of entropy and enthalpy to free energy of binding. Binding enthalpies correlate with ligand polar surface areas suggesting an allowance for charged/polar interactions without enormous energetic penalties for dehydration. In the case of fluvoxamine, which possesses the greatest conformational flexibility yet binds entropically, flexible interaction is implied such that the entropic penalty expected from conformational restriction is limited. Rapid association was observed for all ligands, reflecting low energy barriers and diffusion‐limited binding reactions. The inhibitors bind in a mutually‐exclusive manner with each other as well as with 5‐HT. Taken together, the antidepressant binding site is probably solvent exposed, possibly along the substrate transport pore as predicted from structural modeling based on the leucine transporter.