COMPUTER-ASSISTED MOLECULAR MODELING OF BENZODIAZEPINE AND THYROMIMETIC INHIBITORS OF THE HEPG2 IODOTHYRONINE MEMBRANE TRANSPORTER

T-3 cellular uptake is inhibited in the presence of benzodiazepines (BZs). The structure-activity relationship of BZ inhibition correlates strongly with halogen substitution of the nonfused phenyl ring and indicates that this ring is required for activity. A structure-activity series of thyromimetic (TH) inhibitors of the HepG2 iodothyronine transporter further point out the critical importance of the amino group of the alanine side chain, its L-stereo configuration, and the size of the substituents of the inner and outer phenyl rings. A third series of compounds, reported to interact at related sites, were inactive as HepG2 iodothyronine transport inhibitors, and therefore the potent inhibitors were restricted to the BZ and TH compounds. Using both of these BZ and TH structure-activity series along with computer-assisted molecular modeling techniques, we determined which chemical structural components were important at the transporter interaction site. By superimposing structures from active chemicals, excluding residues from poor inhibitors, and incorporating molecular electropotential data, we developed a five-point model of BZ conformational similarity to the endogenous transporter ligand, L-T-3: the alkyl substitution at the N1 of the BZ ring seems to simulate the alanine side chain of T-3, and the electronegative halogen and oxygen atoms of substituents at R3/R7/R2'/R4' of BZ form a pyrimidal pharmacophore that seems to correspond with the 3-I/5-I/3'-I/4'-OH substituents of T-3, respectively. These points, suggesting a tilted cross-bow formation, may be sites for ligand interaction with the iodothyronine transporter.