摘要:

AbstractThis report examines the development of quantitative structure‐activity relationships (QSAR) in the analysis of ligand muscarinic receptor interactions. Several sets of agonists acting on different tissues (distinct receptor subtypes) are considered. It is shown that QSAR may represent a suitable tool to increase the general understanding of the nature of ligand interactions at receptor sites. The points discussed in the paper are to draw attention to the development of correlations between biological affinity constants and molecular architecture of the ligands which are essential for deriving refined concepts on the topology of muscarinic receptor site

ISSN:0931-8771    

DOI:10.1002/qsar.19920110102

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractEighty‐three thiolcarbamates with fungicidal and herbicidal activities have been analyzed by a partial least squares (PLS) method. A three component PLS2 model based on 5 physicochemical descriptors explains 75.6% of the fungicidal and herbicidal activity data and is highly significant according to the leave‐one‐out procedure. The interpretation of structural requirements for the compounds with both more potent fungicidal and herbicidal activities is quite easy. Candidate thiolcarbamates with both fungicidal and herbicidal activities were proposed based on the PLS2 model. The PLS2 method has a great advantage that it can handle structural descriptor data X and multivariate activity data Y and get a total picture of relationships between X and Y b

ISSN:0931-8771    

DOI:10.1002/qsar.19920110103

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractA QSAR is obtained for affinity towards the gestagenic receptor for a series of 55 progesterone derivatives (r = 0.935), using the MTD‐method, with MTD for steric misfit and f a corrected relative hydrophobicity. Acceptable stability of regression coefficients of vertex attributions are obtained when this QSAR is compared with previous QSAR's for a reduced series of progesterone derivatives and for testosterone derivatives. Acceptable predicted activities for test molecules (r2= 0.71) and acceptable results in a cross validation‐like procedure (r2= 0.76) were obtained. These are strong arguments that our MTD results correspond to some real features of the gestagenic receptor site. In order to explain relative success of the MTD‐method in QSAR's for steroids, as compared to other methods, molecular aspects of the receptor‐effector interaction are discussed in relation to QSAR‐methodology. Recent computational chemistry approaches are based upon drug molecule‐receptor site energy calculations, assuming a fixed conformation for the receptor site. If the drug molecules are “hard” (rigid), the steric misfit with a “soft” (conformationally flexible) receptor site may be avoided by induction of different local conformational ch

ISSN:0931-8771    

DOI:10.1002/qsar.19920110104

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractInhibition of thermolysin andBacillus brevisneutral proteinase (NP) reactions with N‐(3‐(2′‐furyl)acryloyl)glycyl‐L‐leucinamide by organic solvents and some other simple organic compounds (alkanols, aromatic compounds etc., in total 33 substances) was studied. The enzymes showed very similar affinities for the inhibitors in the whole range of Kivariation (3.7 orders of magnitude). A linear dependence with a nearly unitary slope between the pKivalues and log P's of the compounds was found. The inhibitory power of the compounds, whose molecules are longer than those of propanol or benzene, depended on their ability to donate a hydrogen bond. pKi's of the compounds, in which substituents attached to the propyl group or benzene ring are unable to donate the hydrogen bond, fell off the correlation line; the deviation was proportional to the van der Waals volume of the substituent. pKi's of tert‐butanol and cyclohexanol also fell off the correlation line. Geometrical thickness of their molecules exceeds that of the other studied inhibitors; this may explain their lowered affinity for the enzymes. 6,6‐ or 7,5‐bicyclic compounds did not inhi

ISSN:0931-8771    

DOI:10.1002/qsar.19920110105

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractMolecular similarity is a tool for rationalising the biological activities of potential drug molecules. The most useful form of molecular similarity calculations are usually based upon the molecular electrostatic potential and generally use formulae due to Carbo or Hodgkin but these formulae do not give a similarity index which varies linearly with molecular electrostatic potential. Consequently, a new linear index has been proposed and the potential advantages of this index are discussed.

ISSN:0931-8771    

DOI:10.1002/qsar.19920110106

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractExperimental conditions for the derivation of precise RM‐values are examined; the importance and the theoretical background of the extrapolation to modifyer‐free conditions as well as the generally proposed pK‐correction for RMare discussed. Compounds included in this study stem from the following four classes of drugs: antiarrhythmics, β‐blockers, phenothiazines and benzamides.RM‐values of these compounds (determined in acetonitrile/buffer) are compared with experimentally determined (log Pobs, log P*) as well as calculated log P values (∑f, C log P). Best interrelation is found with non‐pK corrected data derived in a buffer to modifyer mixture 50/50. Comparison of the calculative approaches indicates a slight superiority of

ISSN:0931-8771    

DOI:10.1002/qsar.19920110107

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractA novel description of the relationship between bioactivity and hydrophobicity, log(1/ic) = AlogP – BP+const (ic is the isoeffective concentration and P is the partition coefficient) is derived from a model for drug disposition. The function fits experimental bioactivity‐hydrophobicity profiles with a linear ascending part and a sudden drop in bioactivity after reaching the break‐point equally well as the bilinear equation and better than parabola. Due to its simplicity and fast optimization of the adjustable parameters by linear regression analysis the function is especially suitable for the use in multivariable m

ISSN:0931-8771    

DOI:10.1002/qsar.19920110108

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

摘要:

AbstractA complete thermodynamic description of H‐bonding for drug design is proposed. The approach is based on applicability of multiplicative principle to enthalpy (ΔH) and free energy (ΔG) of complex formation by means of Ed(Ea) and Cd(Ca) factors:\documentclass{article}\pagestyle{empty}\begin{document}$$ \Delta {\rm H = 4}{\rm.96(kJ/mole)E}_{\rm a} {\rm E}_{\rm d} $$\end{document}\documentclass{article}\pagestyle{empty}\begin{document}$$ \Delta {\rm G = 2}{\rm.43(kJ/mole)C}_{\rm a} {\rm C}_{\rm d} + 5.70({\rm kJ/mole}), $$\end{document}Where Ed(Ea) and Cd(Ca) characterize the proton donor (acceptor) ability of compounds. The estimation of E and C values for 163 proton donors and 195 proton acceptors was done, making it possible to predict ΔH and ΔG for 31785 reactions. The comparison of these data with experimental ones for 936 reactions was carried out:\documentclass{article}\pagestyle{empty}\begin{document}$$ \Delta {\rm H}_{{\rm calc}} = -0.27(\pm 0.45) + 1.00(\pm 0.02)\Delta {\rm H}_{{\rm exp}} $$\end{document}\documentclass{article}\pagestyle{empty}\begin{document}$$\begin{array}{cccc}{{\rm n = 936}} & {{\rm r = 0.954}} & {{\rm s = 2.70}} & {{\rm F = 9553}} \end{array}$$\end{document}\documentclass{article}\pagestyle{empty}\begin{document}$$ \Delta {\rm G}_{{\rm calc}} = -0.07(\pm 0.12) + 1.00(\pm 0.01)\Delta {\rm G}_{{\rm exp}} $$\end{document}\documentclass{article}\pagestyle{empty}\begin{document}$$ \begin{array}{cccc}{{\rm n = 936}} & {{\rm r = 0.984}} & {{\rm s = 1.11}} & {{\rm F = 28556}}\end{array} $$\end{document}The substituent effect on H‐bonding ability of compounds was considered. It was established that varying of substituents at active sites can alter its proton donor (acceptor) properties over a wide range of Ed(E3, cd(ca) with sufficient overlap between values of factors corresponding to different types of active sites. One could propose this approach to be applied to quantitative estimation of thermodynamic functions of H‐bonding in substrate‐receptor complexes; also for QSAR modelling, where E and C or its linear combination might be used as molecular descriptors characterizing quantitatively the relative H‐bonding ability of biologically active compounds. The second type of applications is used by the authors when modelling QSAR by means of the program package CLARAS (Classification and Recognition of Activ

ISSN:0931-8771    

DOI:10.1002/qsar.19920110109

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19920110110

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19920110111

出版商:WILEY‐VCH Verlag    

年代:1992

数据来源: WILEY