| Diabetes mellitus is a serious threat to human health. It is a group of metabolic diseases in which a person has high blood sugar, either because the body dose not produce enough insulin, or because cells do not respond to the insulin that is produced. TypeⅡdiabetes mellitus (T2DM) is the most common form of diabetes, accounting for 90% of cases diabetes. Due to the complex causes of the diaseas, the treatment of T2DM is very difficult. Therefore, the discovery and design of novel antidiabetic drugs are significant. In the first chapter, a brief introduction about general treatment strategies on antidiabetic drugs and basic concepts of computer-aided drug design was given.As a top antidiabetic target, dipeptidyl peptidaseⅣ(DPP4) was found to be an indirectly approach to control blood glucose level. Inhibition of DPP4 leads to increases the levels of endogenous incretin hormone, such as Glucagon-like peptide-1 (GLP-1), by prolonging its half-life and consequently enhances the beneficial effects of GLP-1 in glucose dependent insulin secretion andβ-cell restoration. The crystal structure of DPP4 demonstrates two possible pathways for the entry and release of substrates and ligands. In the second chapter, conventional and steered molecular dynamics simulations were performed to explore the details of inhibitor Q448 release from the active site of DPP4 via the two potential pathways. The comparisons of force and work together with potentials of mean force results suggested that the side opening might be more favorable for the inhibitor to pass through. Moreover, Glu205-Glu206 and Phe357 were recognized as two "key residues" in the active site for inhibitor binding. Accordingly, suggestions for further inhibitor design were provided.In the second chapter, a multi-step virtual screening strategy was employed to search for novel structures with DPP4 inhibition. From SPECS database, consisting of over 190,000 commercially available compounds,99 virtual hits were picked up and 15 ones were eventually identified to have DPP4 inhibitory activities at 5～50μM. The structures of our compounds were of diversity and novelty. Hence a pharmacophore model was further built to explore their common binding features on the enzyme. The results provided a new pathway for the discovery of DPP4 inhibitors and would be helpful for further optimization of DPP4 inhibitors, too.Protein tyrosine phospatases (PTP) 1B is another target for T2DM, which influences blood glucose level by negatively regulating insulin receptor (IR). Most of its reported inhibitors contain negatively charged moiety due principally to the positively charged catalysis site of PTPIB. In the fourth chapter, we reported series of glycoconjugates as novel PTPIB inhibitors. Molecular docking study elaborated the plausible binding modes of the structurally diverse sugar-based inhibitors with PTPIB. The sugar moiety was favored for the second pTyr-binding site. The prediction for a series of glycoconjugates bearing alkyl chain length-varied bridges between the sugar and (hydroxy)benzoic moieties was proved by biological assays. And a study on a dual PTP1B/Cdc25B inhibitior also provided suggestions for further rational design of PTPIB inhibitors. |
PDF Full Text Request