摘要:

AbstractThe active site regions of thermolysin (TLN) and carboxypeptidase A (CPA) are directly compared by superimposition of the published crystal structures of eight TLN/inhibitor complexes and four CPA‐inhibitor complexes. There is a remarkable similarity in the S′1region of these two zinc metalloenzymes, and it is suggested that this may be a common feature among other enzymes of this class, including the enkephalin‐degrading neutral endopeptidase or “enkephalinase” (NEP‐24.11). Assuming this common feature, the possible geometry of the S′2region of enkephalinase was determined by performing classical potential energy calculations on potent NEP‐24.11 inhibitors. The active conformation of these inhibitors was thus identified as similar to that found in the X‐ray crystal structure of TLN/inhibitor complexes. It is proposed that the active site region of TLN should serve as a reasonable model for that of NEP‐24.11. Extension of the model to the case of angiotensin‐converting enzyme (ACE) showed that this enzyme might have a similar S′1region to the other three enzymes, and allowed further definition of the ACE model previously deve

ISSN:0931-8771    

DOI:10.1002/qsar.19880070102

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY

摘要:

AbstractMolecular and conformational properties of H2‐receptor antagonists were studied by means of the semiempirical MNDO (Modified Neglect of Differential Overlap) approximation. The compounds investigated were cimetidine (N″‐cyano‐N‐methyl‐N′‐[2‐[(5‐methylimidazol‐4‐yl methyl)thio]ethyl]guanidine) analogues, in which the cyanoguanidine moiety was replaced by various other neutral dipolar groups. A strong relation was found between, H2‐antagonistic activity as measured in vitro on the histamine stimulated guinea pig right atrium, one of the components of the overall MNDO dipole moment, and the lipophilic character of the different substituent groups. The dipole moment component points along the direction of the amidine N′H‐bond suggesting the relevance of hydrogen bond formation upon binding of the ligand to the H2‐receptor molecule. This theoretical study demonstrates that the semiempirical quantum chemical MNDO method might be helpful in calculating molecular properties as e.g. dipole moments, both in cases were experimental data are lacking, and in cases where experimental data are obtained under conditions which deviate strongly from the situation in which the ligand most probably is present when bound to the receptor macromolecule. An incorrect use of quantum c

ISSN:0931-8771    

DOI:10.1002/qsar.19880070103

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY

摘要:

AbstractA QSAR analysis has been carried out on a set of local anesthetic drugs structurally related to lidocaine. The surface and the infiltration activities and the acute toxicity have been examined, and their dependence upon structural as well as physico‐chemical parameters has been expressed in terms of both linear and non‐linear models. The results embodied in the correlation equations are discussed at the light of recent theories on the local anesthetic action. In accord with these theories, the hydro‐/lipophilic balance of the molecules has a basic role in modulating the potency of the compounds, also if this property can be “hidden” behind some structural features. Once the contributions of these structural characteristics have been ruled out (by means of indicator variables), the dependence of the biological response on the distribution coefficient can be quantitatively

ISSN:0931-8771    

DOI:10.1002/qsar.19880070104

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY

摘要:

AbstractTo better evaluate, in the context of QSAR studies, new validation techniques such as bootstrapping and crossvalidation and the new analytic technique of partial least squares (PLS), seventeen QSAR results taken from nine recent publications were reexamined using these techniques. The results indicate that bootstrapping and crossvalidation are more powerful indicators of possible chance correlation than are the classical tests based on assumed normal independent distribution of variables. Although PLS will not detect all correlations existing within a set of data, its conservative behavior is particularly valuable when the candidate physicochemical descriptors are numerous and non‐orthogona

ISSN:0931-8771    

DOI:10.1002/qsar.19880070105

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY

摘要:

Abstractσ and π constants for azoxy groups containing electron withdrawing functions have been evaluated. The electrical influence of these groups was separated into an induction and a resonance parameter. A new scale of π substituent constants has been derived analysing log P values of phenyldiazenecarbonitrile 2‐oxide derivatives. It is closely parallel with the π scale obtained from the nitrophenyl substituted s

ISSN:0931-8771    

DOI:10.1002/qsar.19880070106

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19880070107

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY

ISSN:0931-8771    

DOI:10.1002/qsar.19880070101

出版商:WILEY‐VCH Verlag    

年代:1988

数据来源: WILEY