摘要:

AbstractThe factorial design (FD) strategy has been applied within the CoMFA framework to a set of 71 N‐acyl‐L‐aminoacid esters undergoing hydrolysis by α‐chymotripsin. The steric and electrostatic fields of the molecules aligned in their enzyme‐bound conformations have been subjected to Principle Component Analysis (PCA) and three latent variables have been extracted to build up an FD scheme. Two different training sets of 12 compounds have been formed which satisfy the FD criteria. In addition to these two rationally designed series, 50 training sets of 12 structures have been defined through a random selection procedure.A CoMFA model has been derived from each training set by correlating the binding affinity to the enzyme with the ligands' steric and electrostatic fields. The efficiency of the FD approachversusa simple random selection of the structures has been finally assessed by comparing the performances of the different CoMFA models in predicting the binding affinity of 59 ligands not belonging to the training set under consideration. Our results show that in absence of a proper series design strategy the risk of deriving a poorly predictive CoMFA model cannot be

ISSN:0931-8771    

DOI:10.1002/qsar.19940130302

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

摘要:

AbstractThe descriptive multivariate method known as Correspondence Factor Analysis (CFA) was used to establish correlations between the structures of three chemical classes of compounds (triphenyl‐acrylonitriles (TPEs), diphenylethylenes (DPEs), and diphenylalkyls) substituted in theparaposition by either hydroxy or basic groups and their responses in a battery of three biochemical tests, namely the induction of the proliferation of the MCF7human breast cancer cell‐line, the estrogen‐irreversible inhibition of MCF7cell proliferation (herein denoted cytotoxicity), and binding to the estrogen receptor (ER). The power of CFA was illustrated by performing several analyses: (a) Construction of factorial maps that described only the specificity of the response of the TPE population in the tests or both the specificity and amplitude of the response; (b) Use of the factorial maps as mathematical models for the introduction of new variables. These variables were either further biochemical tests (cytotoxicity under different conditions, inhibition of the activation of protein kinase C) on which the TPE population had been screened or further compounds (DPEs and diphenylalkyls). Relationships among the different tests were thus assessed as well as affiliations of the new compounds with TPEs. The analyses revealed the importance of the presence and configuration of hydroxy groups in ER binding and cell proliferation, but also the ability of non‐hydroxylated compounds to induce cell growth independently of their relative affinity for ER. Cytotoxicity could be related to the presence of basic groups but also to resonance of conjugated bis‐para‐hydroxy diphenyl derivatives. Overall, the analyses stressed the complexity of the relationships between growth‐promoting and growth‐inhibitory potential of the test‐compound populations and suggested the involvement of multiple mec

ISSN:0931-8771    

DOI:10.1002/qsar.19940130303

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

摘要:

AbstractA number of chemicals induce a toxic syndrome in male rats – referred to as α‐2‐μ‐globulin nephropathy – which is characterized by an accumulation of the urinary protein α‐2‐μ‐globulin in renal lysosomes, subsequent cytotoxicity and cell death. Borghoffet al.[1] measured the binding affinities to α‐2μ‐globulin for a number of molecules and metabolites recognised as causing α‐2μ‐nephropathy and suggested that binding is dependent on both hydrophobic interactions and hydrogen bonding. Binding affinity to α‐2μ‐globulin has been identified as one of the determinants for α‐2μ‐globulin nephropathy. A QSAR based on these data has been derived by multiple regression analysis relating the binding to negative charge density of the binding molecule and its molecular volume. Data of Bomhardet al.[2] correlating aliphatic and alicyclic hydrocarbon structures with ability to induce renal lysosome accumulation in male rats, were analysed by the technique of principal components analysis applied to the molecular volumes and principal inertial axes of alcohols predicted to be derived from the hydrocarbons. Mapping of the first and second principal components showed clustering of molecules relative to their biological activity. A combination of the two QSARs is useful in identifying molecules with a p

ISSN:0931-8771    

DOI:10.1002/qsar.19940130304

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

摘要:

AbstractThe primary metabolism of caffeine (1,3,7‐trimethylxanthine) is catalyzed by the isozyme P‐450 1A2 which has toxicological relevance because it is involved in the activation of some chemicals to carcinogenic compounds. A theoretical model for the demethylation of caffeine is proposed by means of the study of the molecular electrostatic potential (MEP) distributions of caffeine and other xanthine derivatives that are inhibitors of this metabolic process. Negative zones of these distributions show a common triangular pattern in the xanthine plane. The model proposes that the alignment of the caffeine molecule in the active site is determined by these negative MEP zones. An interesting finding was that all the methyl groups to be removed have at least a MEP minimum at a distance of approximately 3 Å. This feature would explain the preference for the N3demethylation leading to paraxanthine (1,7‐dimethylxanthine) because only this methyl group is placed at a distance of 3 Å from the deepest MEP minimum. Another experimental observation consistent with the proposed model is the inhibition of caffeine demethylation by several 8‐methylxanthines. Among them, 1,3,8‐trimethylxanthine, furafylline (1,8‐dimethyl‐3‐(2‐furfuryl)xanthine) and 1,8‐dimethyl‐3‐phenylxanthine were considered in the present study. The inhibition is explained by the fact that all these compounds have a methyl on C8placed at a distance of 3 Å fr

ISSN:0931-8771    

DOI:10.1002/qsar.19940130305

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

摘要:

AbstractIn QSAR studies of large data sets, variable selection and model building is a difficult, time‐consuming and ambiguous procedure. While most often stepwise regression procedures are applied for this purpose, other strategies, like neural networks, cluster significance analysis or genetic algorithms have been used. A simple and efficient evolutionary strategy, including iterative mutation and selection, but avoiding crossover of regression models, is described in this work. The MUSEUM (Mutation and Selection Uncover Models) algorithm starts from a model containing any number of randomly chosen variables. Random mutation, first by addition or elimination of only one or very few variables, afterwards by simultaneous random additions, eliminations and/or exchanges of several variables at a time, leads to new models which are evaluated by an appropriate fitness function. In contrast to common genetic algorithm procedures, only the “fittest” model is stored and used for further mutation and selection, leading to better and better models. In the last steps of mutation, all variables inside the model are eliminated and all variables outside the model are added, one by one, to control whether this systematic strategy detects any mutation which still improves the model. After every generation of a better model, a new random mutation procedure starts from this model. In the very last step, variables not significant at the 95% level are eliminated, starting with the least significant variable. In this manner, “stable” models are produced, containing only significant variables. A comparison of the results for the Selwood data set (n = 31 compounds, k = 53 variables) with those obtained by other groups shows that more relevant models are derived by the evolutionary approach than by othe

ISSN:0931-8771    

DOI:10.1002/qsar.19940130306

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

摘要:

AbstractTheoretical descriptors for nucleic acids are generated by applying principal component analysis to 3‐D field data of non‐bonded and charge‐charge interaction type. These descriptors are subsequently used to develop quantitative sequence‐property models with good predictability forE. colitranscriptional DNA‐promoter sequences using the method of partial least squares projections to latent structures (PLS). The resulting 3‐D contour maps can be used to investigate requirements for new nucleic acids to be synthesized in order to obtain sequences with altered

ISSN:0931-8771    

DOI:10.1002/qsar.19940130307

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

摘要:

AbstractA new approach called “dynamic” QSAR is introduced to enhance the exploration of active chemicals and relevant molecular descriptors. In contrast to conventional QSAR methods where chemical structure is described by a single, low energy conformer, “dynamic” QSAR simulates the multiplicity of 3‐D molecular shapes that a molecule can assume in complex reaction environments. The core of the new methodology is the coupling of the 3DGEN algorithm which exhaustively generates conformers and a rule‐based system to rapidly screen conformers for desired properties. Hypotheses regarding receptor shape and interaction mechanisms are conveniently incorporated into the screening algorithm. A full array of Stereoelectronic parameters available to OASIS can be combined with conventional topological and physicochemical indices for all conformations and explored using a variety of mathematical and visualization techniques. The “dynamic” QSAR method is illustrated by modeling the acute toxicity of a series of unsaturated a

ISSN:0931-8771    

DOI:10.1002/qsar.19940130308

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19940130309

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19940130310

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19940130301

出版商:WILEY‐VCH Verlag    

年代:1994

数据来源: WILEY