摘要:

AbstractNeurophysins I and II (NPI and NPII) serve in the neurosecretory granules as carrier proteins to the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively. The (NPII/VP)2heterotetramer, believed to be the smallest functional unit, was modelled using a low‐resolution structure information, viz. the Cα‐carbon atom coordinates of the homologous NPII/dipeptide complex (file 1BN2 in the Brookhaven Protein Data Bank) and a recently proposed (from the transfer NOE experiment) NPI‐bound OT structure as template. An all‐atom representation was obtained using standard modelling tools available within the SYBYL suite of programs (by Tripos, Inc.). The starting complex was elaborated for further refinements by two alternative strategies, termed Model I and Model II. Model I consisted of a constrained simulated annealing (CSA) protocol while Model II consisted of carefully elaborated sets of constrained minimizations. Both Models were terminated with a ∼ 100 ps molecular dynamics (MD) in water using the AMBER 4.1 force field. The free homodimer NPII2was obtained by the removal of the two VP subunits from their sites and elaborated according to Model I only. Both models have lead to structures similar to the solid state NPII/dipeptide complex and the recently published the NPII/OT (cross)complex. Nonetheless, Model I as one implementing constrained simulated annealing and thus less amenable to personal bias, is further recommended as a method of choice for the preparation of the starting all‐atom structures for MD. The MD simulations indicated that both in the homodimer and in the heterotetramer the 310helices display increased mobility relative to the remainder of the protein. Also, theC‐terminal domains in the (NPII/VP)2heterotetramer are more mobile than theN‐ terminal ones. In addition to a pair of distinct inter‐monomer attractive contributions, provided by H‐bonds from Ser25O7of one NP unit to Glu81Oϵof the other, nonbonded attractive interactions involving binding site of unit 1(2) and the inter‐mononer interface of unit 2(1) are clearly seen. We speculate that both the increased mobility of the 310helices and carboxyl domains, as well as these interactions may contribute to the allosteric communication between the ligand binding an

ISSN:0931-8771    

DOI:10.1002/qsar.19970160302

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractForty‐two molecules, thirty‐eight milrinone analogues, two lead compounds, amrinone and milrinone, and two commercial products have been studied using chemometrical techniques applied to thirty theoretical descriptors and two biological activities (each one at three different concentrations).PLS Regression was applied both in the usual form PLS‐1, with one response variable, and as PLS‐2, with the contemporary study of more activities in the block of response variables.Regression models (both with the original activities and with log and arctan transforms) were refined by progressive elimination of conformers and of non‐relevant predictors, one‐at‐a‐time, on the basis of the relevance in the regression equation. Different sorts of model refinement gave origin to four chemometrical strategies.Special attention was deserved to the development of validation procedures for the regression analysis, in order to evaluate the true predictive ability of the refined models. The predictive optimization was based on cross‐validation. Complete validation using three sets (training, optimization, external) was applied in one of the strategies. Both optimization and validation were performed in different conditions in order to eliminate the possibility of chance correlation.The severe validation procedures applied prevent underestimate of prediction error, frequently encountered when partial validation procedures are applied.Only one biological activity at the highest concentration can be predicted from the theoretical descriptors with a reasonable prediction error, measured by cross‐validated explained variance. Only volume descriptors have a sure importance in the fin

ISSN:0931-8771    

DOI:10.1002/qsar.19970160303

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractSemi‐empirical molecular modelling calculations of ring rotational energy barriers were carried out for 96 tetrachlorobenzyltoluenes (TCBTs) to provide insight in the possible coplanarity of these compounds, which is required for dioxin‐type toxicity. Comparative calculations were performed for the structurally related polychlorinated biphenyls (PCBs) and polychlorinated diphenylethers (PCDEs). On account of this comparison PCBs, PCDEs and TCBTs were divided into groups of different energy barriers. PCDEs and TCBTs were classified into the same relatively high energy barrier groups. Using the criterion of fitting within a 3 × 10 Å geometry and using structure activity relationships, our results indicate that two out of the 91 coplanar TCBTs can interact with the dioxin (Ah) rec

ISSN:0931-8771    

DOI:10.1002/qsar.19970160304

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractComparative molecular field analysis (CoMFA) using partial least squares (PLS) is a popular method in 3D‐QSAR studies. Although CoMFA has been of general use, it is suboptimal or even useless when nonlinear relationships are observed between field variables and biological activity. Quadratic PLS (QPLS) developed by Woldet al.is an extension of PLS to deal with nonlinear chemical data. In this paper, it is demonstrated that QPLS can be applicable to the 3D field variables in CoMFA. The structure‐activity data of dihydrofolate reductase (DHFR) inhibitors were used as a test example. The resulting QPLS model gave high predictivity with only one component to explain the nonlinear relationships between the electrostatic field variables and inhibitory activity. The loading values of the QPLS model were plotted in 3D space and chemically reasonable contour maps were obtained in accordance with the previous multiple and non‐linear regression (MLR)

ISSN:0931-8771    

DOI:10.1002/qsar.19970160305

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractArtificial neural networks of the backpropagation type with three layers (input, hidden, output) are able to recognize structural molecular features determining the lipophilicity of unionized organic molecules and to directly use the chemical structure for the calculation of the partition coefficient [logP(octanol/water)]. Using a network with three neurons in the hidden layer and binary variables to indicate the presence or absence of atom types and bond types a standard deviation of s = 0.248 was obtained in the correlation between logPobs. and logPcalc. for a small training set of 268 simple organic molecules containing C, H, N, O, S, halogens. For a test set of 50 similar molecules the predicted logP values were satisfactory (s = 0.659).

ISSN:0931-8771    

DOI:10.1002/qsar.19970160306

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

摘要:

AbstractBased on conformational analysis and GRID‐contour calculations we developed a common primary pharmacophore for rolipram analog, nitraquazone and xanthine derivative PDE IV inhibitors. In spite of the structural differences exhibited by the three substance classes we could provide evidence that they share common hydrogen bonding and lipophilic enzyme binding site

ISSN:0931-8771    

DOI:10.1002/qsar.19970160307

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19970160308

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19970160301

出版商:WILEY‐VCH Verlag    

年代:1997

数据来源: WILEY