Human Genetics And Molecular Medicine - Master Dissertation

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    Association of UGT1A6 2 (Ser7Ala) polymorphism with therapeutic response to aspirin in ischemic stroke patients
    (Central University of Punjab, 2018) Kumar, Dharmendra; Munshi,Anjana
    Ischemic stroke occurs due to the formation of thrombus or embolism within the arteries due to platelet aggregation. Aspirin therapy is used for the prevention of secondary stroke. The variant of UGT1A6 (Ser7Ala) gene has been found to be associated with ischemic stroke as well as aspirin resistance. We aim to study the demographic profile of ischemic stroke patients from Malwa region of Punjab and to evaluate the frequency of UGT1A6*2 Ser7Ala polymorphism and correlate it with aspirin resistance and ADRs (if any). We collected 30 samples from confirmed ischemic stroke patients from Guru Gobind Singh Medical College and Hospital in Malwa region of Punjab. DNA was isolated from blood and PCR- RFLP technique was used to evaluate the UGT1A6 gene variant in the patients. mRS value was used to classify patients as responders or nonresponders. 24 patients had TT genotype and 6 patients were found to bear TG genotype. 90% of patients were aspirin responders and 10% were aspirin nonresponders. Since the sample size was too low to identify significant associations, a large number of samples should be screened before coming to a conclusion. However, this preliminary study indicates that UGT1A6*2 (Ser7Ala) variant of UGT1A6 gene might be a risk factor for aspirin resistance in the studied group.
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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.