摘要:

AbstractThe 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 (r2= 0.803, predictive power Q2= 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 (r2= 0.938 and Q2= 0.908). The QSAR studies showed a thioxanthene ring with a ‐CF3substituent 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 with1H‐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 (mirror‐like) orientation entering the lipid bilayer by the ring system suggesting much better fitting of T compared to C to the lipid “M

ISSN:0931-8771    

DOI:10.1002/qsar.19970160102

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractQSAR analysis of racemates is complicated if specific substituent‐receptor interactions and, by that, specific spatial fits to the binding site result in individual but unknown activity differences of enantiomers, and even in structure‐dependent changes of which is the more active configuration. In a first approximation, additivity of substituent contributions should be assumed instead of major conformational effects. Then, Free‐Wilson analysis (FWA) can be used as preprocessing tool to reduce a starting set of all pairs of enantiomers into a final series of the probably (more) active configurations. A stepwise “leave‐one‐isomer‐out” approach is applied, where the model is successively improved by checking all remaining pairs and leaving out one enantiomer, determined by a special criterion of poorest prediction, in each step. The final model is given by the maximal F value. This approach was applied to histamine H1antagonistic activity (pKB, guinea pig ileum) of 19 racemic and six non‐chiral phenyl‐halogenated N‐(diphenylpropyl)‐N′‐(imidazolylpropyl)guanidines. Based on only eight variables because of additivity of meta and para contributions, the starting model with n = 44, r2= 0.29, s = 0.52, F = 1.8, r2‐PRESS = −0.14 has been improved to a final one with n = 31 (only six remaining pairs), r2= 0.84, s = 0.24, F=14.0, r2‐PRESS = 0.65. Additionally, each of the successive series was submitted to CoMFA. Statistical parameters of the parallel CoMFA and FWA models are closely related. QSAR results obtained with both methods correspond to well‐known structure‐activity relationships of diphenhydramine‐like H1antagonists. A direct application of the leave‐one‐isome

ISSN:0931-8771    

DOI:10.1002/qsar.19970160103

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractThe anti‐HIV‐1 activity of some derivatives of 1‐[2‐hydroxyethoxy]‐6‐(phenylthio)thymine(HEPT) is analyzed in relation to their physicochemical and molecular properties. The activities of the compounds are found to be significantly correlated with hydrophobic constant π and the van der Waals volume Vw. The results are found to be useful in discussing the mechanism of drug‐recept

ISSN:0931-8771    

DOI:10.1002/qsar.19970160104

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractMolecular Quantum Similarity Measures (MQSM), which allow quantitative comparison between molecular electronic density distributions, are investigated as a potential source of QSAR parameters. By computing the MQSM for all possible molecular pairs in a given molecular set, a Similarity Matrix is obtained, containing relevant information about the structural relationships within the set. Approximate Overlap‐like MQSM using several computational levels are employed to obtain similarity matrices for three molecular sets, taken as test cases: (1) non‐branched alkanes, (2) Baker triazines, (3) indole derivatives. The similarity matrices have been analyzed by means of PCA and PLS techniques. QSAR regression models were derived in order to fit available property or biological activity data. A reasonably good correlation between properties or activities and the similarity measures has been fo

ISSN:0931-8771    

DOI:10.1002/qsar.19970160105

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractCorrespondence analysis is a variant of principal component analysis for use with categoric data. It has been applied to structural information describing the frequencies of certain molecular features and the skin sensitization potential of a database of organic compounds. Correspondence analysis allows the graphical study of the interrelationship between the relative frequency of structural features of non, weak, moderate and strong sensitizers and the individual class membership. Structural features resulting in protein reactivity are shown to be strongly associated with strong sensitizers; other features, not related to reactivity, are associated with non, or weak, sensitizers. The analysis also indicates structural features whose description is too vague and needs more refinement.

ISSN:0931-8771    

DOI:10.1002/qsar.19970160106

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractThe vapour pressure (VP) is an important physical property of organic compounds for the description of fate and distribution of xenobiotics in the environment. This property was measured for 30 polycyclic aromatic hydrocarbons (PAH) and formulas for VP based on molecular weight and topological indices, respectively, were derived using the technique of Kubinyi and as a second step by regression analysis. A formula for the 30 PAH, considered here, is given.Therein the VP is related to the information theoretical index IdWmean and with a chain‐connectivity index. More specific results are derived for three groups of PAHs. The robustness of the equations is tested by bootstrap analysis. In addition a formula is discussed, which is based on four different incremental factors, a method widely used in physical organic chemistr

ISSN:0931-8771    

DOI:10.1002/qsar.19970160107

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19970160108

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19970160109

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19970160101

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY