Studies On The Structure-activity Relationship Of ACE Inhibitory Tri-peptides With Tyrosine As Terminal

Angiotensin converting enzyme (ACE) inhibitor has always been the hotspot inantihypertensive agents research. Foodborne protein has been attracted widespreadattention because of its significant safety, reliability and the small side effects in thefunction of inhibiting ACE. The model was established based on tripeptides with tyrosineas terminal. Three potential ACE inhibitory tripeptides were synthetized according to themodel, and their inhibitor activities were tested in vitro. The research on microscopicstructure of ACE inhibitory tripeptides was carried out by molecular dynamic and NMR.This thesis consists of three parts as follow:Part I: ACE inhibitory tripeptides with tyrosine were collected from published article.Three models were established using MLR (multiple linear regressions) based on theZ-scales, ISA-ECI, MS-WHIM coded amino acids respectively. The model based on theZ-scales coded showed the best reliability and prediction ability. The inhibitor activities(IC50) of potential ACE inhibitory tripeptides which were not reported were predicted.According to the model, the electrical parameters in the second amino acid of tripeptideshows the biggest influence of inhibitor activities, the second factor was the hydrophobic ofthe first amino acid. Three potential ACE inhibitory tripeptides (IRY, IEY, LEY) weresynthetized for a future testing. Part II: The ACE inhibitor activities of the three new tripeptides were tested by directspectrophotometric measurement, the inhibitor activity of antihypertensive drugs lisinoprilwas tested by the same way. The inhibitor activity of lisinopril was close to the articlereported, which show the method of inhibitor activity test was reliable. The logIC50of IEY,IRY and LEY are-0.203,-0.127and-0.01respectively. The test values are very closed tothe prediction value, which indicated the prediction ability of the model was fine.Part III: The microstructure and weak interaction of the tripeptide was discussed bymolecular dynamic simulation (MD) and nuclear magnetic resonance (NMR). The ACEinhibitory tripeptide in two different solution environment (H2O and DMSO)weresimulated by molecular dynamic software Tinker. Nuclear magnetic resonance experimentsinclude1H-NMR,1H-1H-COSY and2D-NOESY were used to validate the simulation. Theresult of MD and NMR of IEY coincide with each other. In water, extended conformationand semifolded conformation of IEY were observed both, but the extended conformationwas the main conformation; In DMSO, extended conformation was the only conformationof IEY.