STRUCTURAL REQUIREMENTS OF ANGIOTENSIN RECEPTOR: PREFERRED MODIFICATIONS FOR ANTAGONIST DESIGN

Blood pressure and fluid balance are regulated hormonally by renin-angiotensin system (RAS). Influence on this system could be achieved by different compounds that act as angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers and renin inhibitors. The purpose of the present study is to predict the structures of the potent ACE inhibitors on the base of His-Leu peptide structural element of angiotensine I using computational methods. Different modifications were made in the structure of this dipeptide and the energy of binding with the enzyme were calculated. The docking results were analyzed and it was found that along with the important amino acid residue of the receptor molecule Arg167, the Tyr residues (35, 87, 88 and 92) as well as Cys180 areextremely important for the strong binding to the receptor and, accordingly, the manifestation of antagonistic action by the analogues. To block the receptor, the ligand molecule must have an intact terminal carboxyl group and an imidazole nucleus to participate in appropriate interactions. The inclusion of functional groups in the side chains of the amino acid residues of the dipeptide create an additional site for binding to the receptor. With the help of docking, the ligand molecule can be optimized, and this process is fast,  aving the synthesis of many compounds and their biological testing. And finally, the most potent analogues will be synthesized and biologically tested.