Angiotensin-converting Enzyme Inhibitors, Molecular Design

Hypertension grievously imperils the health of human being. It is indicated by authoritative inquiry that, after liberation, the incidence of high blood pressure keeps increasing, and still increasing now. Therefore, developing cardiovascular medicine has wide economy market and positive social effect. In present, there are four kinds of Hypertension medicine: Calcium antagon, β-blocker, Diuretics and Angiotesin converting enzyme inhibitor(ACEI). Among them, the ACEI develop very quickly, and now there are more than ten kinds of ACEI is saling. In order to develop more effective ACEI, a great deal of research on ACE have been carried on and the struction and the function mechanisms of ACEI. For the cardiovascular diseases, it is widely identified that the machanism is rennin-angiotensin system and kallidin i transformation process in body. ACE can catalyze the proteolysis of angiotensin Ⅰto the vasopressor angioensin Ⅱ. The latter is a kind of strong vasoconstrictive substance, and result in high blood pressure. ACEI can ihibit the proteolysis of angiotensin Ⅰ, reduce the biosynthesis of angioensin Ⅱ, which can lower the blood pressure. This research carried out the designation of new ACEI molecule by using Computer-Aided Drug Design method. The main softwares are LigBuilder and AutoDock. The research work including: firstly, analyse the 3D structure of ACE in complex with a known inhibitor linsinopril, and then get the information of active sites; secondly, develop a large number of inhibitor molecules by using GROW and LINK strategys, and screen out better molecules from them; at last, dock these molecules to ACE and pick out the molecule whose docking energy is the lowest. The work is carried on by the assistant of computer, make the best use of the knowledge of ACE and ACEI to direct the design of new ACEI molecule. By doing this, avoided the blindness and saved time and labor. The calculatinoal score indicates that the designed molecules can better bind to ACE, and have high fat soluble. The docking energy is lower than known inhibitor linsionpril as well. The research provides a starting structure for further development of high efficiency ACEI drugs.