Abstract:
O-linked-N-acetyl glucosamine transferase (OGT) is an enzyme which catalyses the product of Hexosamine biosynthetic pathway (HBP). It involves in the normal cell growth. The role of HBP is to control the cell proliferation and hyper OGT in cancer cells. The increased level of OGT, due to high glucose uptake induces cell proliferation in cancers such as breast, colon, prostate, liver etc. Besides this, OGT also up regulates the level of oncogenic factors (C-MYC, NFkβ). Moreover, it involves in the signalling pathway (PI3K, mTOR) and tumour suppressor proteins (P53, MdM2). Whereas inhibition of OGT reduces the hyper O-GlcNAcylation and cell proliferation in cancers. However, targeting hyper OGT in cancer remains poorly understood. In this study, we proposed the docking strategies to get the best binding hypothesis. Due to availability of x-ray crystal structure of OGT in 2018, it is now possible to design small molecular inhibitors that would have promising utility to evade cell proliferation in cancer. As all the targeting compounds were docked at one point. Further, in this project we identified the amino acid residues His920, Thr 921 and 922, Lys 842 responsible for the hydrogen bonding and hydrophobic interactions and they have important role towards the binding of highly active compounds to the target protein. These binding poses were than implemented to molecular dynamics simulation to check the stability of complex via RMSD and hydrogen bond analysis. This MD simulation will result the template selection to generate the possible Pharmacophore model that displayed the accuracy greater than 80% with the hydrogen bond acceptor, hydrogen bond donor and hydrophobic as important pharmacophoric features to which might have the utility to inhibit the OGT protein. Overall, we have developed an integrated virtual screening pipeline that will be used to screen new modulators against OGT to minimize the inhibitory effects. Thus, the proposed mechanism can be used in future for experimental validation.
