| 1. |
- Azuaje, Jhonny, et al.
(författare)
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Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists
- 2015
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Ingår i: Future Medicinal Chemistry. - : Future Science Ltd. - 1756-8919 .- 1756-8927. ; 7:11, s. 1373-1380
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Tidskriftsartikel (refereegranskat)abstract
- Background: A(3)AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A(3)AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A(3)AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A(3)AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure-activity and structure-selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.
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| 2. |
- Betari, Nibal, et al.
(författare)
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Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis
- 2020
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Ingår i: Future Medicinal Chemistry. - : Future Science. - 1756-8919 .- 1756-8927. ; 12:16, s. 1461-1474
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation.Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound1(2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one), which showed high potency (50% inhibition at 98 +/- 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of1showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed.Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.
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| 3. |
- Betari, Nibal, et al.
(författare)
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Synthetic corticosteroids as tryptophan hydroxylase stabilizers
- 2021
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Ingår i: Future Medicinal Chemistry. - : Future Science Ltd.. - 1756-8919 .- 1756-8927. ; 13:17, s. 1465-1474
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Tidskriftsartikel (refereegranskat)abstract
- Background: Clinically, corticosteroids are used mainly for their immune-modulatory properties but are also known to influence mood. Despite evidence of a role in regulating tryptophan hydroxylases (TPH), key enzymes in serotonin biosynthesis, a direct action of corticosteroids on these enzymes has not been systematically investigated.Methodology & results: Corticosteroid effects on TPHs were tested using an in vitro assay. The compound with the strongest modulatory effect, beclomethasone dipropionate, activated TPH1 and TPH2 with low micromolar potency. Thermostability assays suggested a stabilizing mechanism, and computational docking indicated that beclomethasone dipropionate interacts with the TPH active site.Conclusion: Beclomethasone dipropionate is a stabilizer of TPHs, acting as a pharmacological chaperone. Our findings may inspire further development of steroid scaffolds as putative antidepressant drugs.
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| 4. |
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| 5. |
- Grander, D, et al.
(författare)
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Autophagy: cancer therapy's friend or foe?
- 2010
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Ingår i: Future medicinal chemistry. - : Future Science Ltd. - 1756-8927 .- 1756-8919. ; 2:2, s. 285-297
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Tidskriftsartikel (refereegranskat)abstract
- Autophagy is a physiological process that is activated not only in response to stress (e.g., degradation of damaged organelles or nutrient starvation) but also during carcinogenesis and tumor progression. Furthermore, a number of commonly used anticancer drugs activate the autophagic program, a response that, in most cases, suppresses the cytotoxic effects of the drugs, where in some other cases, autophagy promotes drug-induced cell death. Significant progress has been made on delineating the signaling cascades activated during autophagy. A number of known or candidate tumor-suppressor genes that are involved in autophagy have been shown to be activated or inactivated in various cancer types. These genetic perturbations do not only affect carcinogenesis but also the responses of the cancer cells to treatment. The current state-of-the-art with respect to the genes regulating autophagy and the importance of autophagy in the cytotoxic response of cancer treatments will be discussed in this review.
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| 7. |
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| 8. |
- Johansson, Ulf, et al.
(författare)
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The Trade-Off between Accuracy and Comprehensibility for Predictive In Silico Modeling
- 2011
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Ingår i: Future Medicinal Chemistry. - : Future Science. - 1756-8919 .- 1756-8927. ; 3:6, s. 647-663
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accuracy concerns the ability of a model to make correct predictions, while interpretability concerns to what degree the model allows for human understanding. Models exhibiting the former property are many times more complex and opaque, while interpretable models may lack the necessary accuracy. The trade-off between accuracy and interpretability for predictive in silico modeling is investigated. Method: A number of state-of-the-art methods for generating accurate models are compared with state-of-the-art methods for generating transparent models. Conclusion: Results on 16 biopharmaceutical classification tasks demonstrate that, although the opaque methods generally obtain higher accuracies than the transparent ones, one often only has to pay a quite limited penalty in terms of predictive performance when choosing an interpretable model.
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| 9. |
- Johansson, Ulf, et al.
(författare)
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Trade-off between accuracy and interpretability for predictive in silico modeling
- 2011
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Ingår i: Future Medicinal Chemistry. - 1756-8919 .- 1756-8927. ; 3:6, s. 647-663
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accuracy concerns the ability of a model to make correct predictions, while interpretability concerns to what degree the model allows for human understanding. Models exhibiting the former property are many times more complex and opaque, while interpretable models may lack the necessary accuracy. The trade-off between accuracy and interpretability for predictive in silico modeling is investigated. Method: A number of state-of-the-art methods for generating accurate models are compared with state-of-the-art methods for generating transparent models. Conclusion: Results on 16 biopharmaceutical classification tasks demonstrate that, although the opaque methods generally obtain higher accuracies than the transparent ones, one often only has to pay a quite limited penalty in terms of predictive performance when choosing an interpretable model.
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| 10. |
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