[Molecular targets for searching of endothelial-protective substances]

Endothelial dysfunction underlies the development of many cardiovascular diseases. Thus endothelium becomes an independent therapeutic target, and the search of new substances with endothelial-protective action to date is one of the promising tasks for pharmacotherapy and medicinal chemistry. Molecular modeling is an effective tool for solving this problem. Computer chemistry methods use is only possible in combination with detailed information on three dimensional structure and functions of molecular targets: receptors and enzymes, involved in signal transduction inside and outside of endothelial cells. Information on structure and function of various macromolecules involved in vascular tone regulation is collected in the review. The structure of endothelial NO-synthase (EC 1.14.13.39) (eNOS)--enzyme, responsible for the nitric oxide synthesis and involved in vascular tone regulation process is reviewed. The importance of eNOS substrate--L-arginine is underlined in the review in terms of this enzyme activity, regulation, the information on structure and functions of L-arginine transport system is provided. Also different ways of eNOS activity regulation are reviewed, among which are enzyme activation and concurrent inhibition by substances interaction with active center of enzyme, inhibition by caveoline binding with oxigenase domain, and also regulation by phosphorylation of certain amino acids of eNOS by proteinkinase and dephoshphorylation of them by phosphatases. The importance of membrane receptors of endothelial cells as targets for endothelial-protective substances is underlined. Among them are receptors of endothelin, platelet activation factor, prostanoids, bradykinin, histamine, serotonin and protease activated receptors. The important role of potassium and calcium ion channels of vascular cells in endothelial-protective activity is underlined. Macromolecules presented in the review finally are considered as targets for searching for medicinal substances with endothelial-protective activity using proposed ways and methods of molecular modeling.