Human Genetics And Molecular Medicine - Master Dissertation

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    In Silico Design Of Compounds As Sglt2 Inhibitors
    (Central University of Punjab, 2018) Chakravorty, Kamaljyoti; Munshi,Anjana
    SGLT2 inhibitors (SGLT2i) are the current novel therapeutic approach expected to control the growing threat of type 2 diabetes mellitus (T2DM). With comparatively least reported side effects, SGLT2i (gliflozins) have been identified as promising tools to tackle the threat of T2DM. However, studies have also reported these drugs to cause renal impairments and urinogenital infections among certain T2DM patients. The efficacy of an inhibitor is fundamentally determined by the stability of protein-inhibitor complex. Therefore, it is essential to study the binding site residues of SGLT2 in the light of inhibitors' interactions. Structural insights of SGLT2 suggested a competitive inhibition of the ligand glucose (agonist) by the gliflozins. The inhibitory effect of SGLT2i reduces the renal reabsorption of glucose and promotes glycosuria. Consequently, a reduced plasma glucose level prevents the risk of hyperglycemia and further T2DM. In order to design potent inhibitors the structures of the available gliflozins (empagliflozin, canagliflozin, dapagliflozin and ertugliflozin) were analysed. Accordingly, a library of 44 fragment molecules was generated for interactive enumeration. A core ligand structure was designed based on the structural analysis of the gliflozin. A total of 3250 ligand molecules were obtained using schrodinger maestro v11.3. Docking results have shown ligand molecules exhibiting two different modes of inhibition. Set A molecules exhibited glyconic mode of interaction while set B molecules displayed aglyconic mode of interaction at the glucose binding site. The interactions of set B molecules are similar to that of the standard gliflozins and are expected to be less stable. Lesser stability of the protein- iv ligand complex perhaps lead to the reported side effects. On the other hand, set A molecules (with lower docking score) are expected to be much stable in terms of their interactions which differ significantly from that of the standard gliflozins. Therefore, set A molecules are the anticipated potent SGLT2 inhibitors expected to show reduced side effects.