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    Design, synthesis and anti-hyperglycemic assessments of novel 5-benzyli-denethiazolidine-2,4-dione derivatives as PPAR-? agonist
    (Elsevier, 2023) Ali, Amena; Ali, Abuzer; Asati, Vivek; Kaya, Savas; Ahsan, Mohamed Jawed
    The treatment of diabetes mellitus still relies predominantly on peroxisome proliferator-activated receptor-gamma (PPAR-gamma) therapy, known for its effectiveness. In this present study, a novel series of benzylidene-linked thia-zolidine-2,4-dione compounds was conceptualized, synthesized, and subjected to assessment for their potential antidiabetic properties. Notably, among the compounds examined, 5-((Z)-4-(((E)-Propylidene)amino)benzyli-dene)thiazolidine-2,4-dione, designated as 4c, emerged as the most promising candidate, exhibiting the highest PPAR-gamma agonistic activity with an EC50 value of 0.35 +/- 0.52 mu M. Additionally, molecular docking investigations were conducted on twelve 2,4-thiazolidinedione compounds, with a pyrazole moiety incorporated, within the ligand binding domain of PPAR-gamma. Compound 4c, in particular, demonstrated a Glide XP score of-9.104, sur-passing the score of the crystal ligand (Glide XP score =-7.482). Notably, both exhibited similar interactions with key amino acids, including HIE323, SER289, and GLN286. Furthermore, three derivatives (4a-c) with promising PPAR-gamma agonistic activity and favorable molecular docking scores underwent in vivo evaluation for their capacity to lower blood glucose levels using a streptozotocin-induced diabetic mice model. In comparison to the reference drug pioglitazone, Compound 4c displayed commendable in-vivo performance across multiple parameters, encompassing serum HDL, serum LDL, serum total cholesterol, and serum triglyceride levels. Mo-lecular dynamics simulations provided insights into the impact of ligand 4c, indicating its role in enhancing protein stability and rigidity. These findings emphasize its potential as a potent protein inhibitor, thus opening novel avenues for the intelligent design of molecules with high efficacy in the management of hyperglycemia.
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    Screening of Novel Hydroxamic Acid Derivatives as ASM Inhibitors for the Treatment of Depression
    (Wiley-V C H Verlag Gmbh, 2024) Gupta, Shankar; Asati, Vivek; Ali, Amena; Chtita, Samir; Kaya, Savas; Ali, Abuzer
    In the present work, we performed a computational study on hydroxamic acid containing compounds as acid sphingomyelinase (ASM) inhibitors. The study starts from the development of 3D-QSAR and pharmacophore models, which were further taken as a source for the enumeration and virtual screening study. The 3D-QSAR results showed the best statistical model with Q2, R2, and R2 scrambling values of 0.7175, 0.9019, and 0.7128, respectively. The pharmacophore hypothesis generated one of the best hypotheses including five features such as 2 aromatic rings, 2 hydrogen bond donors, and 1 hydrogen bond acceptor. The enumeration study paved the path in the discovery of novel compounds where pharmacophore hypothesis and 3D QSAR study data was used for the identification of novel compounds. Compound 9f_20 showed good docking score -11.399 and binding interactions with amino acids HIP317, ASN316, GLH386, Zn701, Zn702, HIP317, and HIP280 required for ASM inhibitory activity. The virtual screening study was performed on the basis of developed pharmacophore ADDRR_1 where ZINC000013941849 showed good binding interactions with receptor including amino acids Zn701, Zn702, HIP280, LYS103, HIP317, ASN316, and ILE487. ZINC000013941849 with docking score -13.101. The screened compounds may be taken for the further development of novel antidepressant agents. The present work consists of a computational study on hydroxamic acid-containing compounds as sphingomyelinase (ASM) inhibitors. The study starts from the development of 3D-QSAR and pharmacophore models, which are further taken as a source for the enumeration and virtual screening study. The screened compounds may be taken for the further development of novel antidepressant agents. image