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.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Italy.
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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