Design, Synthesis, Activity And Molecular Dynamics Studies Of PTP-MEG2 Inhibitors

Objective:Diabetes mellitus(DM),symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger.It is chronic metabolic disease with high blood sugar levels and itcould cause complications without treatment.The mechanism iseither not enough insulin produced by pancreas or body cells could not respond properly to the insulin produced.Nowadays over 300 million people suffer from diabetes overworld, and the number will reachbillion by 2030, and 4.6 million would die of this.Base on traditional medicines have defects over therapy of type II diabetes,new potential targets need to be found urgently.the PTP-MEG2 inhibitor possesses highly activities and selectivities. It could augmente insulin signaling and improve insulin sensitivity.Our goals are focusing on design and synthesize anti-diabetic lead compounds based on the structure of PTP-MEG2 target enzyme to overcome the sideeffect.Methods : Virtual screening part, a lead hit was obtained from ZINC-druglike database with high docking score and well space conformity. A series of structurally optimized small molecules was obtained by core-hopping method. A dababase of small molecules was established. Base on computer-aided drug design(CADD) & the molecular dockingtechnologies,virtual screening wascarried out. Listedthe docking score andbinding mode, the compounds which show inhibitionto PTP-MEG2 were chosen and after further evaluated, some drug-like molecules wereselected for synthesis. the synthetic routes were designed and the final compounds were obtained through the reactions of Wittig, Sonogashira and Williamson. TLC &LC-MS were employed to check the reaction process. Structures were identified by MS and 1H / 13 C NMR.Workup includes extraction, filtration, column chromatography separation, 42 compounds are obtained. Biological assay was carried out in vitro.Molecular dynamics simulation was performed to study the stability of compound-target complex.Results:A lead hit ZINC36636028 was obtained from ZINC-druglike database with high docking score and well space conformity. APTP-MEG2 antidiabetic compoundsdatabase based on the hit. A series of PTP-MEG2 inhibitors are obtained through virtual screening of the PTP-MEG2-target antidiabetic compounds database.Molecular docking studies show that these compounds are found to form hydrogen bonds and hydrophobic interaction with the key residues of the target,which indicates that these compounds have potential characters of PTP-MEG2-target drug and can be recognized as antidiabetic lead compounds for PTP-MEG2.Insynthetic section, 42 compounds are obtained in all. The target compounds were synthesized through 8-12 steps and structures are confirmed by NMR and MS.The inhibitionof compounds on PTP-MEG2 were performed andthe results shows that some compounds havevery goodinhibitoryeffect on PTP-MEG2.While molecular dynamic simulation, ten nanoseconds routine molecular dynamic simulation is employed to the complex of inhibitor and PTP-MEG2 receptor.By analysis of the trajectory files, inhibitor recognition mechanism was discovered,and this might provide the theoretical evidence to explorer novel PTP-MEG2 receptor inhibitors.Conclusion: This research selected PTP-MEG2 as the target enzyme. The designed compounds were screened using the CADD technology, and 42 final compounds which may have pharmacological activity were synthesized and confirmed by1H-NMR and MS in order to discover lead compound for treating diabetes. The enzyme experiment showed that part of the design of compounds could inhibit PTP-MEG2 enzyme activity having the potential research value. Molecular dynamicssimulationof the active compound with PTP-MEG2 was carried out, and the interactions of compounds with the enzymes were interpreted in a dynamic manner,which prepare for the discovery of novel hypoglycemic agents.