Identification of Novel <i>S-</i>Adenosyl-<scp>l</scp>-Homocysteine Hydrolase Inhibitors through Homology-Model-Based Virtual Screening, Synthesis, and Biological Evaluation

Khare, Prashant; Gupta, Amit K.; Gajula, Praveen Kumar; Sunkari, Krishna Y.; Jaiswal, Anil K.; Das, Sanchita; Bajpai, Preeti; Chakraborty, Tushar Kanti; Dube, Anuradha; Saxena, Anil Kumar

doi:10.1021/ci2005862

Cited by 17 publications

(13 citation statements)

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“…[23] In the present work, we evaluated the 28 substituted aryl thiazolyl phenylsulfonamides by docking the compounds in the PTP1B binding site using the GLIDE 5.6 module of the Schrodinger software package. [23] In the present work, we evaluated the 28 substituted aryl thiazolyl phenylsulfonamides by docking the compounds in the PTP1B binding site using the GLIDE 5.6 module of the Schrodinger software package.…”

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“…Earlier we reported the successful use of docking studies to understand the structure-activity relationships and elucidate the essential structural requirements for molecules acting on the same receptor/enzyme. [23] In the present work, we evaluated the 28 substituted aryl thiazolyl phenylsulfonamides by docking the compounds in the PTP1B binding site using the GLIDE 5.6 module of the Schrodinger software package. [24] All the ligands were prepared with the LigPrep 2.3 application using an OPLS 2005 force field.…”

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Synthesis, Structure–Activity Relationship and Docking Studies of Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine Phosphatase 1B Inhibitors

et al. 2012

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28 to 1—not bad odds: Protein tyrosine phosphatase 1B (PTP1B) is a promising target for the treatment of type 2 diabetes. Aryl thiazolyl phenylsulfonamides were synthesized and screened against PTP1B in vitro. Compounds exhibiting >48 % inhibition were then evaluated in a streptozotocin‐induced (STZ) rat model of diabetes, identifying one compound with efficacy comparable to that of metformin. Finally, docking studies were used to explain the observed structure–activity relationships.

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Synthesis, Structure–Activity Relationship and Docking Studies of Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine Phosphatase 1B Inhibitors

et al. 2012

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“…Further proteomic characterization of this subfraction revealed a number of immunogenic proteins , including AdoHcy. This was identified as a drug target in other organisms , but in this study AdoHcy was developed as recombinant protein and was eventually reassessed for immunogenicity using lymphocytes/PBMCs of treated Leishmania ‐infected hamsters and patients.…”

Section: Discussionmentioning

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Immunoprotective responses of T helper type 1 stimulatory protein-S-adenosyl-L-homocysteine hydrolase against experimental visceral leishmaniasis

Khare

Jaiswal

Tripathi

et al. 2016

Clinical and Experimental Immunology

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SummaryIt is well known that a patient in clinical remission of visceral leishmaniasis (VL) remains immune to reinfection, which provides a rationale for the feasibility of a vaccine against this deadly disease. In earlier studies, observation of significant cellular responses in treated Leishmania patients as well as in hamsters against leishmanial antigens from different fractions led to its further proteomic characterization, wherein S-adenosyl-Lhomocysteine hydrolase (AdoHcy) was identified as a helper type 1 (Th1) stimulatory protein. The present study includes immunological characterization of this protein, its cellular responses [lymphoproliferation, nitric oxide (NO) production and cytokine responses] in treated Leishmania-infected hamsters and patients as well as prophylactic efficacy against Leishmania challenge in hamsters and the immune responses generated thereof. Significantly higher cellular responses were noticed against recombinant L. donovani S-adenosyl-L-homocysteine hydrolase (rLdAdoHcy) compared to soluble L. donovani antigen in treated samples. Moreover, stimulation of peripheral blood mononuclear cells with rLdAdoHcy up-regulated the levels of interferon (IFN)-g, interleukin (IL)212 and down-regulated IL-10. Furthermore, vaccination with rLdAdoHcy generated perceptible delayed-type hypersensitivity response and exerted considerably good prophylactic efficacy ($70% inhibition) against L. donovani challenge. The efficacy was confirmed by the increased expression levels of inducible NO synthase and Th1-type cytokines, IFN-g and IL-12 and down-regulation of IL-4, IL-10 and transforming growth factor (TGF)-b. The results indicate the potentiality of rLdAdoHcy protein as a suitable vaccine candidate against VL.

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“…In the present study, steric, electrostatic, hydrophobic, H-donor and H-acceptor similarity fields were calculated using the default CoMSIA settings (Probe with charge +1, radius 1 Å, grid spacing 2 Å, attenuation factor of 0.3 and hydrophobic, hydrogen-bond doner, and hydrogenbond acceptor as +1). where SD is the sum of squared deviation of each biological activity from the mean, and PRESS is the sum of squared deviations between the actual and the predicted activities [30].…”

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Integrated ligand and structure-based investigation of structural requirements for silent information regulator [SIRT1] activation

Gupta

Choi

2018

Preprint

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A series of imidazothiazole and oxazolopyridine derivatives as human silent information regulator (SIRT1) activators were subjected to the integrated 2D and 3D QSAR approaches. The derived 3D QSAR models yielded high cross validated q 2 values of 0.682 and 0.628 for CoMFA and CoMSIA respectively. The non-cross validated correlation values of r 2 training = 0.89; predictive r 2 test = 0.69 for CoMFA and r 2 =0.87; predictive r 2 test =0.67 for CoMSIA reflected the statistical significance of the developed model. The steric, electrostatic, hydrophobic and hydrogen bond acceptor interactions have been found important in describing the variation in human SIRT1 activation. Further, 2D QSAR model for the same dataset yielded high statistical significance and derived 2D model's parameters corroborated with 3D model in terms of features. The developed model was also validated through the available active conformation structure of SIRT1. Developed models may be useful for the identification of potential novel human SIRT1 activators as therapeutic agent. Keywords: SIRT1 activators, imidazothiazole and oxazolopyridine derivatives, 3D QSAR, 2D QSAR, CoMFA and CoMSIA. heterocyclic analogs [19], 1,4-dihydropyridine analogs [20], resveratrol analogues [21, 22], and some quinoxaline analogs [23]. The crystal structure of human SIRT-1 protein with its small molecule activator was unknown until recently [24], thus few ligand-based studies have been reported on SIRT1 activators [25,26]. However, no quantitative validation of the reported models has been reported in these studies. Our past successful efforts of integrated ligand-and structure-based drug discovery on other targets [27,28,29,30] encouraged us to use this approach in the presented project. We herein report a ligand-based 3D QSAR models using known SIRT1 activators and its validation through available crystal structure of SIRT1. Methodology DatasetThe QSAR studies have been performed on a dataset of fifty compounds belonging to Imidazothiazole and Oxazolopyridine class having human SIRT1 activation potency with EC1.5 values ranging from 0.16µM to 130µM [18,19]. Activation in the assay was measured as the concentration of compound required to increase the enzyme activity by 50% (EC1.5). The EC1.5 values were converted into negative logarithm of EC1.5 (pEC1.5) for the use in the QSAR studies.The fifty compounds in the dataset were rationally distributed into a training set of 26 molecules and a test set of 24 molecules to generate the QSAR models and evaluate the predictive ability of the developed models respectively. The chemical structures along with their biological activity of all the dataset compounds have been shown in Figure1, Table1 and Table 2.Please insert Figure 1 about here. Table 1 about here. Please insert

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Identification of Novel S-Adenosyl-l-Homocysteine Hydrolase Inhibitors through Homology-Model-Based Virtual Screening, Synthesis, and Biological Evaluation

Cited by 17 publications

References 37 publications

Synthesis, Structure–Activity Relationship and Docking Studies of Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine Phosphatase 1B Inhibitors

Synthesis, Structure–Activity Relationship and Docking Studies of Substituted Aryl Thiazolyl Phenylsulfonamides as Potential Protein Tyrosine Phosphatase 1B Inhibitors

Immunoprotective responses of T helper type 1 stimulatory protein-S-adenosyl-L-homocysteine hydrolase against experimental visceral leishmaniasis

Integrated ligand and structure-based investigation of structural requirements for silent information regulator [SIRT1] activation

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