1,721,028 research outputs found
2-Pyridone derivatives as inotropic agents: synthesis, pharmacology and molecular modeling study
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Studio computazionale di complessi di intercalazione al buio DNA-psoraleni Pavia, 27-29 maggio 1999
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Toward the identification of the cardiac cGMP inhibited-phosphodiesterase catalytic site
No full textCyclic nucleotide phosphodiesterases (PDEs) comprise a complex group of enzymes; five major PDE families or
classes with distinctive properties have been identified. Among these a great deal of interest has recently been
focused on the so called cGMP-inhibited low Km cAMP phosphodiesterase (cGI PDE) or PDE III. A number of
positive inotropic agents, including the well-known milrinone, display a specific inhibition of PDE III as primary
mechanism of action. Recent studies have been carried out to develop a pharmacophore model of the PDE III
active site. We therefore performed molecular modelling and 3D-SAR studies so as to better define structural
requirements for potent and selective enzymatic inhibition. The DISCO (DIStance COmparison) strategy has been
applied on a set of compounds taken from literature and a milrinone analogue previously synthesized by us, all of
which are characterized by a marked inotropic effect but with varying degrees of enzyme selectivity. A common
pharmacophoric model was derived, validated and considered as starting point to perform a 3D-SAR study using
the GRID force field and PCA (Principal Component Analysis) with the aim of rationally designing more selective
inhibitors. This paper presents the results of this theoretical approach
2-Pyridone derivatives as inotropic agents: synthesis, pharmacology and molecular modeling study
No full textZupan's descriptors in QSAR applied to the study of a new class of cardiotonic agents
No full textRecently a new class of molecular descriptors has been proposed and used in QSAR with simulated data and with regression performed by neural networks. In the present paper these descriptors (Zups, from the name of their author, Juri Zupan) have been slightly modified and then applied to a real data set with the aim of studying the structure-activity relationships of a new class of cardiotonics. Forty-one molecules (thirty-seven milrinone analogues, the two lead compounds amrinone and milrinone, and two commercial products) have been studied using classical chemometrical techniques such as PCA (Principal Components Analysis) and PLS (Partial Least Squares regression). Zups describe essentially the local geometry of the molecules. They show promising performances, as compared with other classical geometrical descriptors (as molecular volume, etc.), both in that regards the overall performances, measured by the C.V. Explained variance and in the interpretability of the regression equation. However they have not all the requirements of a good structure representation. Moreover some selectable parameters seem to have a great importance, so that the refinement of the regression model requires time and the evaluation step must be performed in condition of full-validation, because predictive optimisation is used in the selection of parameters, and the final model must be checked on molecules never used to refine the model or, in this case, the parameters of the structure representation
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