Estimation of the three-dimensional pharmacophore of ligands for rat multidrug-resistance-associated protein 2 using ligand-based drug design techniques.

PURPOSE

Multidrug-resistance-associated protein 2 (Mrp2) shows a broad substrate specificity toward amphiphilic organic anions. This study identified key functional groups of ligand molecules for binding to rat Mrp2, determined their relative locations, and examined substrate specificity through receptor mapping using three-dimensional (3D) quantitative structure-activity relationship (3D-QSAR) analysis.

METHODS

Ligand-binding conformations were estimated using conformational analysis (CAMDAS) and molecular superposition (SUPERPOSE) methods to clarify the substrate specificity of rat Mrp2 in relation to 3D ligand structures.

RESULTS

Two types of binding conformations of ligands for rat Mrp2 were identified. 3D-QSAR comparative molecular-field analysis (CoMFA) revealed a statistically significant model for one type, in which the steric, electrostatic, and log P contributions to the binding affinity for rat Mrp2 were 63.0%, 33.4%, and 3.6%, respectively (n = 16, q2 = 0.59, n = 3, r2 = 0.99, and s = 0.08).

CONCLUSIONS

The 3D pharmacophore of ligands for rat Mrp2, and the ligand-binding region of rat Mrp2, were estimated. Ligand recognition of rat Mrp2 is achieved through interactions in two hydrophobic and two electrostatically positive sites (primary binding sites). The broad substrate specificity of rat Mrp2 might result from the combination of secondary (two electrostatically positive and two electrostatically negative sites) and primary binding sites.