Toward the identification of the cardiac cGMP inhibited-phosphodiesterase catalytic site.
Cyclic nucleotide phosphodiesteras (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 K(m) 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.
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Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Italy.
Boggia
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001665:Binding Sites; D002316:Cardiotonic Agents / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D017076:Computer-Aided Design; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D009206:Myocardium / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human