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 (B Zs). The structure-activity relationship of BZ inhibition correlates s trongly with halogen substitution of the nonfused phenyl ring and indi cates that this ring is required for activity. A structure-activity se ries of thyromimetic (TH) inhibitors of the HepG2 iodothyronine transp orter further point out the critical importance of the amino group of the alanine side chain, its L-stereo configuration, and the size of th e substituents of the inner and outer phenyl rings. A third series of compounds, reported to interact at related sites, were inactive as Hep G2 iodothyronine transport inhibitors, and therefore the potent inhibi tors were restricted to the BZ and TH compounds. Using both of these B Z and TH structure-activity series along with computer-assisted molecu lar modeling techniques, we determined which chemical structural compo nents were important at the transporter interaction site. By superimpo sing structures from active chemicals, excluding residues from poor in hibitors, and incorporating molecular electropotential data, we develo ped a five-point model of BZ conformational similarity to the endogeno us 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 elect ronegative halogen and oxygen atoms of substituents at R3/R7/R2'/R4' o f 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, su ggesting a tilted cross-bow formation, may be sites for ligand interac tion with the iodothyronine transporter.