A general pharmacophore model of P-glycoprotein (P-gp) drugs is proposed that is based on a highly diverse data set and relates to the verapamil binding site of the protein. It is derived from structurally different drugs using the program GASP. The pharmacophore model consists of two hydrophobic points, three hydrogen bond (HB) acceptor points, and one HB donor point. Pharmacophore patterns of various drugs are obtained, and different binding modes are presumed for some of them. It is concluded that the binding affinity of the drugs depends on the number of the pharmacophore points simultaneously involved in the interaction with P-gp. On the basis of the obtained results, a hypothesis is proposed to explain the broad structural variety of the P-gp substrates and inhibitors: (i) the verapamil binding site of P-gp has several points that can participate in hydrophobic and HB interactions; (ii) different drugs can interact with different receptor points in different binding modes.
Multidrug resistance, MDR, is a major obstacle in the chemotherapeutic treatment of cancer. MDR can be reversed by drugs that vary widely in their chemical structure and main biological action. Many efforts are directed to find out the relationships between the structure and MDR reversal effect of these drugs. In this review we try to summarize the results of a variety of studies on identification of structure-activity relationships, SARs, and quantitative SARs, QSARs, of different MDR reversing drugs. As any reasonable (Q)SAR study relies on a real or putative presentation about the mechanism of action of the studied compounds, the most significant MDR mechanisms revealed till now are shortly discussed. Special attention is paid to P-glycoprotein, P-gp, related MDR as the most experimentally and clinically tested form of drug resistance. The currently proposed models of P-gp functioning and mechanisms of MDR modulation are presented. Problems that can arise in (Q)SARs studies are discussed in advance to allow the reader to judge on possible pitfalls. The physicochemical and structural properties of MDR modulators as found by different research groups are commented and summarized. From the discussed studies it can be concluded that the careful selection of relevant structural and biological data processed with appropriate QSAR and especially 3D-QSAR methods, is a promising approach to structure-activity studies of MDR reversers.
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.
A homology model of P-glycoprotein based on the crystal structure of the multidrug transporter Sav1866 is developed, incorporated into a membrane environment, and optimized. The resulting model is analyzed in relation to the functional state and potential binding sites. The comparison of modeled distances to distances reported in experimental studies between particular residues suggests that the model corresponds most closely to the first ATP hydrolysis step of the protein transport cycle. Comparison to the protein 3D structure confirms this suggestion. Using SiteID and Site Finder programs three membrane related binding regions are identified: a region at the interface between the membrane and cytosol and two regions located in the transmembrane domains. The regions contain binding pockets of different size, orientation, and amino acids. A binding pocket located inside the membrane cavity is also identified. The pockets are analyzed in relation to amino acids shown experimentally to influence the protein function. The results suggest that the protein has multiple binding sites and may bind and/or release substrates in multiple pathways.
The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane phospholipids. This could lead directly (through changes in membrane permeability and fluidity) and/or indirectly (through inhibition of P-glycoprotein phosphorylation via inhibition of the phosphatidylserine-dependent protein kinase C or changes in the conformation and functioning of the membrane-integrated proteins via changes in the structure organization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artificial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the literature) and their ability to interact with phosphatidylserines. Trans- and cis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupromazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction of trans- and cis-flupentixol with the phospholipids studied are suggested to be responsible for their different MDR-reversing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MDR-reversing ability. Amiodarone showed very strong interactions with phosphatidylserines and is recommended for further MDR-reversal studies.
Quinazolinones, indolo- and pyrrolopyrimidines with inhibitory effects toward ABCB1 (P-gp) and ABCC1 (MRP1) transporters were studied by pharmacophore modeling, docking, and 3D QSAR to describe the binding preferences of the proteins. The pharmacophore overlays between dual and/or highly selective inhibitors point to binding sites of different topology and physiochemical properties for MRP1 and P-gp. Docking of selective inhibitors into the P-gp binding cavity by the use of a structural model based on the recently resolved P-gp structure confirms the P-gp pharmacophore features identified, and reveals the interactions of some functional groups and atoms in the structures with particular protein residues. The 3D QSAR analysis of the dual-effect inhibitors allows satisfactory prediction of the selectivity index of the compounds and outlines electrostatics as most important for selectivity. The results from the combined modeling approach complement each other and could improve our understanding of the protein-ligand interactions involved, and could aid in the development of highly selective and potent inhibitors of P-gp and MRP1.
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