Browsing by Author "Jaswal, Shalini"

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    Dual aromatase-steroid sulfatase inhibitors (DASI's) for the treatment of breast cancer: a structure guided ligand based designing approach
    (Taylor and Francis Ltd., 2022-12-13T00:00:00) Singh, Yogesh; Jaswal, Shalini; Singh, Satwinder; Verma, Sant Kumar; Thareja, Suresh
    Dual aromatase-steroid sulfatase inhibitors (DASIs) lead to significant deprivation of estrogen levels as compared to a single target inhibition and thereby exhibited an additive or synergistic effect in the treatment of hormone-dependent breast cancer (HDBC). Triazole-bearing DASI�s having structural features of clinically available aromatase inhibitors are identified as lead structures for optimization as DASI�s. To identify the spatial fingerprints of target-specific triazole as DASI�s, we have performed molecular docking assisted Gaussian field-based comparative 3D-QSAR studies on a dataset with dual aromatase-STS inhibitory activities. Separate contours were generated for both aromatase and steroid sulphates showing respective pharmacophoric structural requirements for optimal activity. These developed 3D-QSAR models also showed good statistical measures with the excellent predictive ability with PLS-generated validation constraints. Comparative steric, electrostatic, hydrophobic, HBA, and HBD features were elucidated using respective contour maps for selective target-specific favourable activity. Furthermore, the molecular docking was used for elucidating the mode of binding as DASI�s along with the MD simulation of 100 ns revealed that all the protease-ligand docked complexes are overall stable as compared to reference ligand (inhibitor ASD or Irosustat) complex. Further, the MM-GBSA study revealed that compound 24 binds to aromatase as well as STS active site with relatively lower binding energy than reference complex, respectively. A comparative study of these developed multitargeted QSAR models along with molecular docking and dynamics study can be employed for the optimization of drug candidates as DASI�s. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
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    Research progress on 2,4-thiazolidinedione and 2-thioxo-4-thiazolidinone analogues as aldose reductase inhibitors
    (Elsevier B.V., 2022-07-18T00:00:00) Kharyal, Ankush; Ranjan, Sanjeev; Jaswal, Shalini; Parveen, Darakhshan; Gupta, Ghanshyam Das; Thareja, Suresh; Verma, Sant Kumar
    Diabetes-associated complications are a major global health concern. In diabetics, the increased accumulation of sorbitol, produced via over activated polyol pathway, from glucose by the action of aldose reductase (AR, ALR2, or AKR1B1), has been associated with life-threatening co-morbidities. Aldose reductase is crucial in detoxifying certain hazardous aldehydes. However, aldose reductase overexpression in the hyperglycemic state results in microvascular and macrovascular diabetic complications through the consequences of the activated polyol pathway. Accordingly, aldose reductase inhibition has been identified as a viable strategy for dealing with diabetes-associated complications, and it has been put under investigation by various researchers around the world. 2,4-Thiazolidinedione (TZD) and its bio-isosteric analog 2-thioxo-4-thiazolidinone (rhodanine) have been explored as potential inhibitors of aldose reductase to find new molecules. The current review provides a comprehensive insight into the development and medicinal chemistry of TZD and rhodanine derivatives as aldose reductase inhibitors during the last twenty years (2002�2021). Here, the synthetic strategies, SAR, and binding mode of various compounds, Quantitative structure activity relationship (QSARs) are discussed with an emphasis on structural changes to the both moieties for optimizing/designing potent target-specific inhibitors, which is expected to be beneficial for the further design and discovery of newer agents for the treatment of diabetic complications. In addition, the patents on TZDs and rhodanine derivatives as aldose reductase inhibitors are summarized to illustrate the current status. � 2022 Elsevier B.V.