Molecular modeling of triazine type MDR modulators using CoMFA and CoMSIA approaches.

In the present study a series of 30 triazine derivatives was investigated by 3D QSAR methods with respect to their MDR reversing activity in vitro. Two approaches were applied and compared: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular models with good predictive power were derived using steric, electrostatic and hydrophobic fields of the compounds. The results indicated the dominant role of the electrostatic and hydrophobic fields for MDR reversing activity of the investigated modulators. The obtained statistical parameters (Qcv2, Qpr2) showed that the CoMFA and CoMSIA models have similar predictivity. The CoMSIA models were slightly better than the CoMFA ones and obtained with lower number of principal components. The models were graphically interpreted using CoMFA and CoMSIA contour plots. The structural regions responsible for the differences in anti-MDR activity were analyzed in respect to their electrostatic and hydrophobic nature. An easier interpretation of the CoMSIA contour plots was noticed.

Structure-activity relationships of multidrug resistance reversers.

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.

Inhibition of UDP-glucuronosyltransferase by 5'-O-amino acid and oligopeptide derivatives of uridine: structure-activity relationships.

The inhibitory effect of a series of 5'-O-amino acid and oligopeptide derivatives of uridine on rat liver UDP-glucuronosyltransferase (UGT) activities was investigated using two assay systems. A quantitative structure-activity relationship (QSAR) study was performed. The compounds include a lipophilic residue linked to the nucleoside by a variable spacer. Moreover, half of the derivatives have two spacers linked to the uridine moiety. Compound 1, a serine derivative of isopropylideneuridine, was found to be the most potent inhibitor of both 4-nitrophenol (4-NP) and phenolphthalein (PPh) glucuronidation, with an I50 of 0.45 mM and 0.22 mM, respectively. Kinetic studies with this substance revealed a mixed type of inhibition towards 4-NP and UDP-glucuronic acid, with apparent Ki values of 150 microM and 120 microM, respectively. The dipeptide derivatives 11-14 exhibited a low activity against 4-NP conjugation. However, a marked suppression of PPh glucuronidation was found with compounds 11 and 13. Generally, compounds with two spacers are more inhibitory against the UGT activities studied. The QSAR analysis outlined the significance of the spacers with a minimum length of 5 atoms and lipophilic residues linked to them for the inhibitory effect of the compounds. The most significant contribution to this effect is given by the six-atom spacer for both 4-NP and PPh substrates. 4-NP converting UGT isoforms seem to respond more specifically to the inhibitors: a five-atom for the first and six-atom for the second spacer enhance binding to both 4-NP and PPh conjugating isoenzymes, while a long second spacer contributes to inhibitor binding to UGT isoforms only converting PPH.

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.

Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability.

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.

Threshold stimulation and accommodation of the Hodgkin-Huxley axon.

The charge-duration and strength-duration relations for just threshold rectangular stimuli were numerically investigated for the Hodgkin-Huxley axons of different lengths and different membrane capacitances under normal conditions and blockage of the development of accommodative processes. Two linear portions could be distinguished on the charge-duration curve. One of them followed the Weiss law. The other one represented a portion of a straight line passing through the zero point of the coordinates. The slope of the second portion was determined by the charge for very short stimuli (Q0), the slope of the first portion, and the maximum time to excitation (tau max). The rheobase reflected the slope of the second portion. Upon varying the fibre length the slope of the first and the second linear portions and the rheobase changed. The membrane capacitance substantially affected both the value of Q0 (as in the case of myelinated fibres) and the rheobase. The accommodative processes affected the Q0, the slope of the first line, tau max, and, consequently, the rheobase. The effect of potassium activation was stronger than that of sodium inactivation. The slope of the first line, tau max, and the rheobase might be considered more comprehensive indicators of the accommodative processes than the usually used indicators.

BACOMP--database of bioactive compounds for structure-activity relationship.

BACOMP database is presented for structure-activity relationship (SAR) investigations; it was realized on a BK-1300 general purpose microcomputer using the MICRO-SETOR network database management system. Some general considerations of database design are given and the models and facilities for a development of a microcomputer-based SAR oriented database are described. The database contains the following information for the bioactive compounds: chemical structures, biological activities, trade names, reference numbers and information sources. For computer representation of chemical structures SAR oriented language is used. The database software includes: system software, data capture and data editing software, information retrieval and data processing applications. The software development is done in FORTRAN IV and MACRO assembly language. The programs are written in a completely interactive mode. The information retrieval software includes 12 functions giving an information for the database as a whole and for a single compound as well. The data processing software includes 8 functions for finding common structural fragments among compounds with similar biological activity and for estimating a structural similarity between different compounds. The functions are selected from corresponding screen MENUs. The function realization results are framed as appropriate screen formats and the receipt of hardcopies is available. The database can be used to develop predictive methods in respect of the investigated biological activity.