Department Of Human Genetics And Molecular Medicine

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Subject: search.filters.subject.SGLT2 inhibitors

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    �The pharmacological profile of SGLT2 inhibitors: Focus on mechanistic aspects and pharmacogenomics�
    (Elsevier B.V., 2021-05-11T00:00:00) Kaur, Prabhsimran; Behera, Bidwan Sekhar; Singh, Sandeep; Munshi, Anjana
    Diabetes, characterized by high glucose levels, has been listed to be one of the world's major causes of death. Around 1.6 million deaths are attributed to this disease each year. Persistent hyperglycemic conditions in diabetic patients affect various organs of the body leading to diabetic complications and worsen the disease condition. Current treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4(dipeptidyl peptidase-4) and GLP-1 (glucagon-like peptide) analogs. However, many side effects contributing to the devastation of the disease are associated with them. Sodium glucose co-transporter-2 (SGLT2) inhibition has been reported to be new insulin-independent approach to diabetes therapy. It blocks glucose uptake in the kidneys by inhibiting SGLT2 transporters, thereby promoting glycosuria. Dapagliflozin, empagliflozin and canagliflozin are the most widely used SGLT2 inhibitors. They are effective in controlling blood glucose and HbA1c levels with few side effects including hypoglycemia or weight gain which makes them preferable to other anti-diabetic drugs. However, treatment is found to be associated with inter-individual drug response to SGLT2 inhibitors and adverse drug reactions which are also affected by genetic variations. There have been very few pharmacogenetics trials of these drugs. This review discusses the various SGLT2 inhibitors, their pharmacokinetics, pharmacodynamics and genetic variation influencing the inter-individual drug response. � 2021 Elsevier B.V.
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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.