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Molecular targets in the search for endothelium-protecting compounds

Abstract

Impairment of endothelial function forms basis for many cardiovascular diseases, therefore today it becomes an independent target for therapeutic action, and the search for new compounds possessing endothelium-protective properties is one of the prospective goals of the pharmacotherapy and medicinal chemistry. An efficient instrument to solve the problem is the use of methods of molecular modeling. Application of the methods is possible only if detailed information on three-dimensional structure and function of molecular targets—receptors and enzymes responsible for signal transduction both inside and outside endothelial cells—is available. In the review we collected the data on the structure and functions of various macromolecules involved in the process of regulation of vascular tone. The structure of endothelial NO-synthase (EC 1.14.13.39) (eNOS) responsible for synthesis of nitrogen oxide and involved in the process of vascular tone regulation is described. The importance of its substrate, L-arginine, from the point of view of eNOS activity regulation is emphasized; the data on structure and functions of L-arginine transport system are presented. Also, various pathways of eNOS activity regulation are described, including activation and competitive inhibition through binding of exogenous substances in its active center and inhibition through caveolin binding at eNOS oxygenase domain among them, as well as regulation by means of phosphorylation of individual eNOS amino acid residues by protein kinases and their dephosphorylation by phosphatases. The importance of membrane receptors of endotheliocytes as targets for substances possessing endothelium-protective activity is emphasized. Receptors of endothelin, thrombocyte activation factor, prostaglandins, bradykinin, histamine, serotonin, and protein kinase-activated receptors are among them. The importance of calcium and potassium ion channels in vessel cells for endothelium protection is emphasized. Finally, the macromolecules discussed in the review are considered as targets in the search for endothelium-protective therapeutic agents by the proposed approaches and methods of molecular modeling.

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Abbreviations

eNOS:

endothelial NO synthase

H4B:

tetrahydrobiopterin

CaM:

calmodulin

CAT:

cationic amino acid transporter

mCAT and hCAT:

mouse and human CAT

PKA:

protein kinase A

PP1 and PP2A:

serine/threonine phosphoprotein phosphatases

PKB/Akt:

protein kinase B

PKC:

protein kinase C

cAMP:

cyclic adenosine monophosphate

D/D:

dimerization/docking domain of protein kinase A

PH:

pleckstrin homology domain of protein kinase B

PI3 kinase:

phosphatidylinositide-3 kinase

DAG:

diacylglycerol

PS:

phosphatidylserine

RACK:

receptor for activated C-kinase

ψRACK:

pseudo-RACK (a region of regulatory PKC domain similar by structure with RACK)

sGC:

soluble guanylate cyclase

PAF:

platelet activation factor

PAR:

protease-activated receptors

PDGF:

platelet-derived growth factor

PDGFR:

PDGF receptor

5-HT:

serotonin (5-hydroxytryptamine)

SKCa, IKCa, and BKCa :

small, intermediate, and large calciumactivated potassium channels

QC/MM:

combination of quantum chemistry and molecular mechanics methods

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Correspondence to A. A. Glushko.

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Original Russian Text © A.A. Glushko, A.V. Voronkov, M.V. Chernikov, 2014, published in Bioorganicheskaya Khimiya, 2014, Vol. 40, No. 5, pp. 515–527.

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Glushko, A.A., Voronkov, A.V. & Chernikov, M.V. Molecular targets in the search for endothelium-protecting compounds. Russ J Bioorg Chem 40, 477–487 (2014). https://doi.org/10.1134/S1068162014050069

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  • DOI: https://doi.org/10.1134/S1068162014050069

Keywords

  • endothelium
  • enzyme
  • eNOS
  • receptor
  • ion channel
  • regulation