Several peptides with hypocholesterinemic properties were investigated in order to reveal structure-activity relationships. The semi-empirical AM1 method and molecular dynamics were used to determine common structural properties of these peptides. A mathematical model of the structure-activity relationship was obtained. According to this model, a hydrophobic part of these peptides is a required structural element for their biological activity. The proline acts as a key component in these compounds.Hypocholesterinemia is one of the primary risk factors for damage to coronary arteries that has been linked to the development of various cardiovascular diseases [1,2]. Treatment of such diseases comprises decreasing the level of circulating cholesterol and its synthesis, which involves mevalonic acid.The biosynthesis of mevalonate in tissues involves 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), two molecules of nicotinamide-adenine-dinucleotide (NADH) or its close analog nicotinamide-adenine-dinucleotide phosphate (NADPH), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR). The activity of this enzyme is the rate-determining step in the biosynthesis of cholesterol. It is controlled specifically by cholesterol and other products synthesized with mevalonate involvement [3][4][5].HMGR can be inactivated by dehydration [6-8], phosphorylation [9-12], or application of inhibitors [13][14][15]. The last are currently being extensively investigated [16][17][18][19][20]. Therefore, several peptides with hypocholesterinemic properties were isolated from soy-protein glycinin. The three peptides Leu-Pro-Tyr-Pro, Leu-Pro-Tyr-Pro-Arg (LPYPR), and Ser-Pro-Tyr-Pro-Arg were synthesized chemically based on the amino-acid sequences obtained. Their hypocholesterinemic activities were investigated [21]. Then, another sequence, namely Ile-Ala-Val-Pro-Gly-Glu-Val-Ala (IAVPGEVA), was identified during enzymatic decomposition of glycinin by pepsin [22].We synthesized seven peptides [Ile-Ala-Val-Pro (IAVP), Leu-Ile-Ala-Val-Pro (LIAVP), Ile-Ala-Val-Pro-Gly-Glu-Val-Ala (IAVPGEVA), Leu-Ile-Ala-Val-Pro-Gly-Glu-Val-Ala (LIAVPGEVA), Ile-Ala-Val-Pro-Thr-Gly-Val-Ala (IAVPTGVA), Leu-Ile-Ala-Val-Pro-Thr-Gly-Val-Ala (LIAVPTGVA), and Leu-Pro-Tyr-Pro-Arg (LPYPR)] that retained the IAVP fragment in all peptides and also LPYPR for comparison with previous investigations and analyzed their conformations. An in vitro test for measuring HMGR inhibition showed that all synthesized peptides possessed hypocholesterinemic properties. According to the results, the IC 50 for IAVP, IAVPTGVA, and IAVPGEVA were measured as 59.3, 93.3, and 123.5 µM, respectively. For LIAVPGEVA, LPYPR, LIAVP, and LIAVPTGVA at 200 µM, the percent HMGR inhibition was 62.3, 33.7, 17.5, and 12.4%, respectively. In the present work, which is a continuation of previous investigations, we attempted to find a structure-activity relationship of the synthesized peptides using the bioactivities, conformational analysis, and quantum-chemical calculations of their structures.The activity as a function...

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