Screening And Anti Tuberculosis Activity Of Targeting AHAS Enzyme Inhibitors

In recent years,the clinical detection of multidrug-resistant Mycobacterium tuberculosis is rising,especially clinic TB strains of Extensively drug-resistant tuberculosis(MDR-TB)and multidrugresistant tuberculosis(XDR-TB)are found more and more,which results in a pessimistic situation of TB prevention,control and treatment.In recent years,the number of effective anti-Mycobacterium tuberculosis drugs is quite low,so it is quite urgent for the research and development of new anti-tuberculosis drug targets.Acetylcarboxylic acid synthase(AHAS)Acetohydroxyacid synthase(AHAS)is an indispensable key enzyme in bacteria,mainly catalyzed by pyruvate in the synthesis of acetoacetic acid in bacteria,which are the most critical enzymes for the biosynthetic pathways of some branched chain amino acids,such as isoleucine and valine.(Duggleby,RG,et al.J.Biochem.Mol.Biol.2000,33(1),1-36).This pathway that catalyze and synthesize amino acids occur only in the body of plants or microorganisms,not in animals.At present,AHAS enzymes have been used as one of the most important and effective targets for herbicide development.The application of AHAS enzymes has been widely used.High performance herbicides targeting AHAS enzymes have many kinds of herbicides such as sulfonylurea and pyrimidine salicylic acid Class and so on.Domestic and foreign studies have shown that AHAS inactivation of bacteria in vivo is an excellent new choice for the effective inhibition of the growth of Mycobacterium tuberculosis,and it also shows thatinhibition of AHAS activity can be an ideal target for anti-tuberculosis drug design.AHAS is limited to expression in plants,bacteria and fungi,and enzymes in humans and animals do not exist homologous,suggesting that inhibition of AHAS activity will not affect human normal life activities.The development of inhibitors in the field of anti-tuberculosis has a good application prospects.In recent years,human beings have made great achievements in structural biology,which makes some of the fungi and plant AHAS crystal structure is interpreted.Through the interpretation of the crystal structure of the enzyme,the use of computer virtual screening technology for targeted screening and design of AHAS inhibitors become a reality.Targeting screening of AHAS inhibitors helps to further explore and study the molecular mechanisms of the interaction between macromolecule targets and small molecule compounds and find some highly specific,high-performance bacterial inhibitors that accelerate the research of targeted drugs,which help the development of precision medicine.In this study,we prepares to use molecular level docking in the computer virtual compound library to find a series of high performance AHAS inhibitors.Compounds with better inhibitory effects have been shown to have a very strong inhibitory effect on the growth of Mycobacterium tuberculosis using preliminary experiments.Based on the structure of yeast AHAS,the computer-homology model of TB-AHAS was used to screen the Maybridge and Specs organic chemical structure database,and the rationalized drug design was found on the basis of GLIDE program.A class of new benzoate compounds,such compounds have a strong inhibitory activity against bacterial AHAS,especially against Mycobacterium tuberculosis is also very strong.This experimentdemonstrates that benzoic acid esters compounds can inhibit the growth of Mycobacterium tuberculosis by inhibiting the activity of AHAS by supplementing some of the branched chain amino acids with cells.In conclusion,the research of targeted AHAS inhibitor and its anti-tuberculosis effect have a good application prospect and practical value.We have discovered a series of more active AHAS inhibitors through computer technology.And then these new compounds from the cell level,the media level,as well as the experimental animal level were respectively studied,so that the selected AHAS inhibitor has a higher application value for the treatment of various clinical drug-resistant and pan-resistant tuberculosis.Combined with cytotoxicity test,we finally get high-activity,low-toxicity,easy-synthesis new compounds and we will evaluate the possibility of its development as new anti-tuberculosis drug lead.