Application of QSAR analysis to organic anion transporting polypeptide 1a5 (Oatp1a5) substrates.

Organic anion transporting polypeptide 1a5, Slco1a5 (previously called Oatp3, Slc21a7) is a multispecific transmembrane transport protein that belongs to the OATP/SLCO superfamily of solute carriers. It is expressed in several epithelial barriers such as the small intestine and the choroid plexus where it might play an important role in the disposition of numerous endogenous and exogenous organic compounds. Since the molecular basis of the multispecificity of Oatp1a5 is not known and the three-dimensional structure not solved yet, we used three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques to obtain topological information on the substrate binding site of the protein. We aligned a heterogeneous data set of 18 Oatp1a5 substrates using the Genetic Algorithm Similarity Program (GASP) and performed comparative molecular field analysis (CoMFA) using this alignment. This resulted in a reasonable QSAR model including steric and electrostatic fields with a leave-one-out cross-validated r(cv)2 value of 0.705 and a no-cross-validated regression coefficient r2 value of 0.949. Based on the derived model we identified new potential Oatp1a5 substrates and confirmed their predicted apparent affinity values experimentally.