Combinatorial Pharmacophore Modeling of Multidrug and Toxin Extrusion Transporter 1 Inhibitors: a Theoretical Perspective for Understanding Multiple Inhibitory Mechanisms

摘要: A combinatorial pharmacophore (CP) model for Multidrug and toxin extrusion 1 (MATE1/SLC47A1) inhibitors was developed based on a data set including 881 compounds. The CP comprises four individual hypotheses, HHR1, DRR, HHR2 AAAP, which can successfully identify the MATE1 with an overall accuracy around 75%. emphasizes importance of aromatic ring hydrophobicity as two important structural determinants inhibition. Compared Organic Cation Transporter 2 (OCT2/ SLC22A2), functional related transporter MATE1, hypotheses AAAP PRR5 are suggested to be responsible their ligand selectivity, while HHR common recognition pattern dual series analysis molecular sizes matching different representative docking indicated that small HHR1 DRR involve in competitive inhibition, relatively large noncompetitive inhibition by locking conformation changing MATE1. In light results, hypothetical inhibiting transporting mediated proposed.