Molecular Modeling of Phenothiazines and Related Drugs As Multidrug Resistance Modifiers:  A Comparative Molecular Field Analysis Study

Abstract

A set of 40 phenothiazines, thioxanthenes, and structurally related drugs with multidrug resistance modulating activity in tumor cells in vitro were selected from literature data and subjected to three-dimensional quantitative structure-activity relationship study using comparative molecular field analysis (CoMFA). More than 350 CoMFA models were derived and evaluated using steric, electrostatic, and hydrophobic fields alone and in combination. Four alignment strategies based on selected atom pairs or field fit alignment were compared. Several training and test sets were analyzed for both neutral and protonated drug forms separately. Each chemical class was trained and tested individually, and finally the classes were combined together into integrated models. All models obtained were statistically significant and most of them highly predictive. All fields contributed to MDR reversing activity, and hydrophobic fields improved the correlative and predictive power of the models in all cases. The results point to the role of hydrophobicity as a space-directed molecular property to explain differences in anti-MDR activity of the drugs studied.

Structure–Activity Relationships of Tariquidar Analogs as Multidrug Resistance Modulators

“…In contrast to logP, the hydrophobic indices, generated by CoMSIA, showed high correlations; the hydrophobic field alone produced models with q 2 =0.718 (27). This observation is in agreement with our previous studies of different classes of first-generation MDR modulators that pointed to the role of hydrophobicity as a space-distributed molecular property for the MDR modulating effect (51,52). It should be noticed that, in contrast to the previous generations of modulators, the predictive ability of the hydrophobic field alone remains relatively low, and the same has been detected in the 3D QSAR study of anthranilamide analogs (39).…”

Three-Dimensional Quantitative Structure-Activity Relationships of Inhibitors of P-Glycoprotein

“…In 1997, the first 3D-QSAR analysis of phenothiazines and related drugs known to be P-gp inhibitors was described previously (Pajeva and Wiese, 1997). This was followed by Hansch-type QSAR studies with propafenone analogs (Salem et al, 1998;Tmej et al, 1998), CoMFA studies of phenothiazines and related drugs (Pajeva and Wiese, 1998a), CoMFA studies of propafenone analogs (Pajeva and Wiese, 1998b), and simple regression models of propafenone analogs Schmid et al, 1999). These latter models confirmed the relevance of hydrogen bond acceptors and the basic nitrogen for inhibitors Schmid et al, 1999) and multiple hydrogen bond donors in substrates 2.5 to 4.6 Å apart (Seelig, 1998).…”

Development of empirical molecular interaction models that incorporate hydrophobicity and hydropathy. The HINT paradigm

“…While the performance of the HINT field in CoMFA can be tuned with a variety of adjustable parameters, one can not a priori expect that the statistical measures of a 3D QSAR model will always be enhanced by the inclusion of the hydropathic field. However, in a few recent CoMFA studies, e.g., by Pajeva and Wiese [36], the HINT field was a significant component of the final model(s). The emerging general rule is that hydrophobic/hydropathic fields will be more applicable in cases where hydrophobic interactions are significant in the binding mode, or where membrane transport is encoded in the biological measure.…”

“…The most significant application of these maps, however, is that they can be imported into 3D QSAR programs such as CoMFA [32] as hydropathic/hydrophobic fields to supplement the standard complement of steric and electrostatic field types. Since we first reported the HINT/CoMFA interface numerous studies have been performed using HINT [33][34][35][36][37][38] as well as other lipophilic field models [39,40] with 3D QSAR. Our experience is mixed.…”