Virtual Screening And Synthesis Of Novel INOS And COX-2 Dual-Target Inhibitors

Modern drug research and development mainly concentrated on designing single target drug moleculars targeting on specific pathological processes.However,as the human body is a complex network system,the occorrence and processing of the disease involve multiple links in the network.Drugs designed to act on individual molecular targets usually can not combat multigenic diseases such as cancer,or diseases that affect multiple tissues or cell types such as diabetes.With the emergence and development of systems biology,multi-target drugs provide a new way for drug discovery.These multi-target drugs can generate synergies through acting on different targets,so that the total effect is greater than the effect of single-target drugs.Multi-target drug therapy can overcome many of the limitations of single-target drugs and adjust multiple links in the network system of disease,which thus reduces drug resistance and achieves ideal therapeutic effect.Inducible nitric oxide synthase(iNOS)and cyclooxygenase-2(COX-2)are playing important roles in the process of inflammation and cancer,and much attention have been paid to their functions and the relationship between them.Although many researches about their respective single-target inhibitors have been reported,most of them are discontinued because of side effects.Under these conditions,more and more researchers start to work on dual-targets inhibitors targeted COX-2 and iNOS.In this paper,both ligand-based drug design and receptor-based drug design are carried out to search dual-targets iNOS and COX-2 inhibitors.The ligand-based approach employ single target iNOS and COX-2 inhibitors to build 3D-QSAR model respectively.Then we conduct virtual screening through these two 3D-QSAR models with the aided of molecular docking.After organic synthesis and bioactivity analysis,we obtain two noval lead compounds 2029 and 2030.The receptor based method employ docking to virtual screen compounds in Xianhe Yanling recipe and find two natural molecules with good Glide Score.Also,these two compounds possess the similar scaffold.These may be helpful to the design of novel dual-targets iNOS and COX-2 inhibitors in the future.