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- Pyrrole (1)
- Pyrrolovesamicol (1)
- VAChT (1)
- Vesamicol (1)
Pyrrolovesamicols - synthesis, structure and VAChT binding of two 4-fluorobenzoyl regioisomers
(2012)
This Letter describes the synthesis of two regioisomers of a new class of vesamicol analogs as possible
ligands for imaging the vesicular acetylcholine transporter in future PET studies. The two pyrrolovesamicols
(±)-6a and (±)-6b were synthesized by nucleophilic ring opening reaction of a tetrahydroindole epoxide
precursor with 4-phenylpiperidine. The reaction mechanism of the synthesis was studied by HPLC
and the molecular structures were determined by X-ray structure analysis. Unexpected low binding affinities
to VAChT (Κi = 312 ± 73 nM for (±)-6a and Κi = 7320 ± 1840 nM for (±)-6b) were determined by competitive
binding analysis using a cell line stably transfected with ratVAChT and (–)-[3H]vesamicol.
Hands-off linear interaction energy approach to binding mode and affinity estimation of estrogens
(2013)
With this work we target the development of a predictictive model for the identification of small molecules which bind to the estrogen receptor alpha and, thus, may act as endocrine disruptors. We propose a combined thermodynamic approach for the estimation of preferential binding modes along with corresponding free energy differences using a linear interaction energy (LIE) ansatz. The LIE model is extended by a Monte Carlo approach for the computation of conformational entropies as recently developed by our group. Incorporating the entropy contribution substantially increased the correlation with experimental affinity values. Both squared coefficients for the fitted data as well as the more meaningful leave-one-out cross-validation of predicted energies were elevated up to rFit2 = 0.87 and qLOO2 = 0.82, respectively. All calculations have been performed on a set of 31 highly diverse ligands regarding their structural properties and affinities to the estrogen receptor alpha. Comparison of predicted ligand orientations with crystallographic data retrieved from the Protein database pdb.org revealed remarkable binding mode predictions.