The Bio-Rational Design And Synthetic Of Inhibitors Based On The Target Enzyme SP-HMGR

There are250million people suffering from pneumococcal pneumonia every year in China, in which125,000people died of pneumonia. Streptococcus pneumoniae is the major factor lead to meningitis, suppurative otitis media in infants and young children, endocarditis, sepsis and other infectious diseases. With the sulfa drugs and penicillin and other antimicrobial agents have been brought forth in1939and1940, pneumonia has been controled and alleviated at a certain degree. However, people gradually found that the body’s physiological trauma caused by Streptococcus can not be treated by penicillin. Moreove, penicillin could not kill Streptococcus pneumoniae completely. long-term use of antibiotics will lead to strain resistance which makes the treatment of pneumonia become more difficult. Therefore, it is important to develop a new drugs that can kill Streptococcus pneumoniae.Isoprenoid is necessary for the life processes of Streptococcus pneumoniae, Streptococcus pneumonia use the mevalonate pathway for the synthesis of IPP. And we choose the HMG-CoA reductase, which catalyzes the conversion of mevaonate to HMG-CoA, enabling the organism to use mevalonate as its sole source of carbon, as the target. This paper contains the following content:The first chapter made an overview about the3-hydroxy-3-methyl-glutaryl coenzyme A reductase （HMGR） and the research status of Class-I HMGR and Class-Ⅱ HMGR.The second chapter describes the theory and calculation methods used in the course of the study.In chapter three, homology modeling of the crystal structure of Streptococcus pneumoniae on the basis of the HMGR crystal structure of the Pseudomonas. we analyzed the important amino acids in the active cavity and design small molecules using lovastatin as reference compound structure, then screening20small molecules by molecular docking,In chapter four, we select one of these compounds in organic synthesis due to the docking results, and the activity part of the carboxylic acid are mainteined,and synthesized four other derivative compounds. Finally, we get five compounds and test the biological activity of them. This paper mainly based on the biological structure of Streptococcus pneumoniae, rational design for some small molecules.First theoretically designed some possible inhibitors of small molecules, through the synthesis of compounds, from the biological experiments demonstrated. Found that the inhibitory rate of CY₃5_M1molecule better than lovastatin. It’s maybe a potential inhibitor. Therefore, we can make further transformation and modification in order to get a higher inhibitory rate for the SP-HMGR.