QSAR and molecular modelling of catamphiphilic drugs able to modulate multidrug resistance in tumors

被引:36
作者
Pajeva, IK
Wiese, M
机构
[1] UNIV HALLE WITTENBERG, DEPT PHARM, D-06120 HALLE, GERMANY
[2] BULGARIAN ACAD SCI, CTR BIOMED ENGN, BG-1113 SOFIA, BULGARIA
来源
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS | 1997年 / 16卷 / 01期
关键词
multidrug resistance modifiers; catamphiphilic drugs; thioxanthenes; drug-membrane interaction; QSAR; Free-Wilson model; multiple linear regression; genetic algorithm; NMR analysis; molecular modelling; COMFA;
D O I
10.1002/qsar.19970160102
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The Free-Wilson approach was applied to two groups of catamphiphilic multidrug resistance (MDR) modifiers using classical multiple linear regression (MLR) and genetic algorithms (GA) for feature selection. In the first group (17 thioxanthenes) the side chain length between the ring system and tertiary nitrogen, the type of the tertiary nitrogen substituent and the stereoisomery were found to be significant for anti-MDR activity both by MLR and GA (r(2) = 0.803, predictive power Q(2) = 0.652). In the second data set (17 phenothiazines and related drugs) the ring system type, the stereoisomery, the side chain type, and the ring substituent kind in position two contributed significantly (r(2) = 0.938 and Q(2) = 0.908). The QSAR studies showed a thioxanthene ring with a -CF3 substituent in position two, a piperazine moiety with a 4-bond distance from the ring system and trans-isomery to be optimal for MDR reversal. Based on these results molecular modeling of trans-(T) and cis-flupentixol (C) was performed assuming that the 2 to 3-fold difference in MDR reversing activity of T compared to C might be related to different preferable conformations in the membrane lipid environment. Among all conformations generated by the SYBYL systematic search routine those comprising local energy minima were selected and optimized with semiempirical quantum chemistry methods. The optimized conformations were compared with H-1-NMR analysis results on drug conformations in lipid environment, some of them corresponded excellently. The electrostatic and lipophilic fields of T and C were compared to identify molecular properties related to the activity difference. The results demonstrated that T and C could have a different (mirrorlike) orientation entering the lipid bilayer by the ring system suggesting much better fitting of T compared to C to the lipid ''MDR-reversal receptor''.
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页码:1 / 10
页数:10
相关论文
共 30 条
[1]  
CHAMBERS TC, 1992, MOL PHARMACOL, V41, P1008
[2]  
CORNWELL MM, 1991, MOL CELLULAR BIOL MU, P229
[3]  
DAHL SG, 1991, THERAPIE, V46, P453
[4]   STRUCTURAL-CHANGES BY SULFOXIDATION OF PHENOTHIAZINE DRUGS [J].
DAHL, SG ;
KOLLMAN, PA ;
RAO, SN ;
SINGH, UC .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1992, 6 (03) :207-222
[6]  
FORD JM, 1990, CANCER RES, V50, P1748
[7]  
FORD JM, 1989, MOL PHARMACOL, V35, P105
[8]  
FORD JM, 1990, PHARMACOL REV, V42, P156
[9]   BIOLOGICALLY-ACTIVE CONFORMERS OF PHENOTHIAZINES AND THIOXANTHENES - FURTHER EVIDENCE FOR A LIGAND MODEL OF DOPAMINE D2 RECEPTOR ANTAGONISTS [J].
FROIMOWITZ, M ;
CODY, V .
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (15) :2219-2227
[10]   COMPARATIVE MOLECULAR-FIELD ANALYSIS OF THE ANTITUMOR-ACTIVITY OF 9H-THIOXANTHEN-9-ONE DERIVATIVES AGAINST PANCREATIC DUCTAL CARCINOMA-03 [J].
HORWITZ, JP ;
MASSOVA, I ;
WIESE, TE ;
BESLER, BH ;
CORBETT, TH .
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (06) :781-786