MOLECULAR MODELING OF PHENOTHIAZINES AND RELATED DRUGS AS MULTIDRUG-RESISTANCE MODIFIERS - A COMPARATIVE MOLECULAR-FIELD ANALYSIS STUDY

A set of 40 phenothiazines, thioxanthenes, and structurally related dr ugs with multidrug resistance modulating activity in tumor cells in vi tro were selected from literature data and subjected to three-dimensio nal quantitative structure-activity relationship study using comparati ve molecular field analysis (CoMFA). More than 350 CoMFA models were d erived and evaluated using steric, electrostatic, and hydrophobic fiel ds alone and in combination. Four alignment strategies based on select ed atom pairs or field fit alignment were compared. Several training a nd test sets were analyzed for both neutral and protonated drug forms separately. Each chemical class was trained and tested individually, a nd finally the classes were combined together into integrated models. All models obtained were statistically significant and most of them hi ghly predictive. All fields contributed to MDR reversing activity, and hydrophobic fields improved the correlative and predictive power of t he models in all cases. The results point to the role of hydrophobicit y as a space-directed molecular property to explain differences in ant i-MDR activity of the drugs studied.