Molecular modeling study of the multidrug resistance modifiers cis- and trans-flupentixol

Recent drug-membrane interaction and quantitative structure-activity relationship studies of thioxanthenes and related compounds acting as multidrug resistance (MDR) modifiers pointed to the importance of the stereoisomery for their MDR reversing activity. Therefore a molecular modeling study of trans-(T) and cis-flupentixol (C) was performed in order to elucidate the observed discrepancy between equal binding potency to P-glycoprotein and different MDR reversing activity of the two stereoisomers. The results show that the 2 to 3-fold difference in MDR reversing activity of T compared to C might be related to a different orientation of the molecules in the membrane lipid environment. From the conformations generated by the SYBYL systematic search procedure those comprising local energy minima were selected and further optimized with semiempirical quantum chemistry methods. From the optimized conformations those that corresponded to 1H NMR results on drug conformations in lipid environment were selected for further molecular modeling studies. The electrostatic and lipophilic fields of T and C were compared in order to identify molecular properties related to the activity difference. The results show that the electrostatic fields of the drugs when similar in shape are dissimilar and that the lipophilic and hydrophilic regions are clearer separated in T in comparison with C. This imposes a better fitting of T compared to C to membrane lipid environment in accordance with the observed higher interaction strength of T with phospholipids.