Molecular modeling studies on the active binding site of the blood–brain barrier choline transporter

In silico predictive model to determine vector-mediated transport properties for the blood–brain barrier choline transporter

“…As it has been already suggested that the BBB-ChT pore is extremely important for a translocation of positively charged drugs across the BBB,22 the analyzed active substances occupied negatively charged portions of the pore within the same binding cavity close to the center of the transporting channel (Figure 6). In accordance with our results, the hypothetical model for the choline transporter binding site20 explains this phenomenon due to strong ionic interaction between the trimethylammonium moiety of ligand and corresponding amino acid residues of protein. In addition, bulk cavity methyl acceptors might play some role to establish a conformational congruence with ligand methyl groups and potentiate the BBB-ChT affinity.…”

“…The expected values for the comparison were 90% (522 residues) and 7% (41 residues), respectively, for the same regions obtained elsewhere, from the literature 18,19. The BBB-ChT-active/inactive chemical compound database, where most of them are positively charged, included 93 molecules compiled from different literature sources12,20–22 in the PubChem BioAssay server. Among them, 44 molecules (47.3%) were the BBB-ChT binders (active substances); 49 molecules (52.7%) were the BBB-ChT nonbinders (inactive substances).…”

“…The first ten BBB-ChT-active bis-pyridinium cyclophanes were determined by their binding affinity to the BBB-ChT in a rat brain and were assessed according to their inhibition of [ 3 H] choline uptake 21. The other 29 various molecules, comprising four active and 25 inactive compounds, were analyzed by the same uptake assay, involving in situ brain perfusion studies of male rats 20. Also, 17 bis-azaaromatic quaternary ammonium salts, among them 15 active and two inactive molecules, were synthesized as ligands for the BBB-ChT protein 22…”

“…The selection was based on the Ki values for choline (Ki choline ), which were in the range of 41–42 μM for the active bis-pyridinium cyclophanes, bis-azaaromatic quaternary ammonium salts, and various molecules from the 3D-QSAR dataset,20 in contrast to the Ki choline of 0.68 μM for ammonium analogs. Regardless of the moderate correlation coefficient ( r 2 =0.47) between the pKi pred values, calculated from the appropriate ΔG bind parameters and Ki exp for both algorithms (Figure 5A and B), it was previously reported that scoring tests on 90 protein-ligand complexes from the Protein Data Bank demonstrated a statistically significant correlation even with r 2 in the range from 0.45 to 0.55, respectively 32…”

Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer

“…The identification of a lead compound was completed using previously reported methods [10–12]. Because the crystal structure of the BBB choline transporter has not yet been determined, we developed a surrogate model which could be used in virtual screening.…”