3D-pharmacophore analyses of transporter ligands for drug discovery studies in consideration of pharmacokinetics

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It is important for the effective drug design and discovery to consider the optimization of the pharmacokinetics from the initial stage of pharmaceutical developments. It is a key point in the current rational drug design and development to identify three-dimensional pharmacophores of the transporter ligands and analyze transporter-ligand interaction, because the transporter proteins express on various histionic cell membranes such as gastrointestinal, brain, liver, kidney to play an important role for the transport of drugs.In this study, we utilized the ligand-based drug design techniques developed in our laboratory to analyze three-dimensional quantitative structure-activity relationships (3D-QSAR) for the ligands of human Organic Cation Transporter 1 (hOCT1) and carry out the comparative study with a 3D-QSAR model generated from other methods. As a result, we were able to get the 3D-QSAR model with a good statistic (q^2 value) by analysis using our techniques. The three-dimensional pharmacophore of hOCT1 ligand obtained from this study consists of a hydrogen bond donor and three hydrophobic atomic groups. This three-dimensional pharmacophore is similar to one obtained from the other methods, but it is shown that our 3D-QSAR model is statistically better than one from other methods for the data set (test set) to evaluate the quality of the model. Thus it is thought that our 3D-QSAR model is a fine model with high predictivity of biological activity for non-homologous compounds which have various structures.