| 1. |
- Areias, Filipe, et al.
(author)
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2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists : The 6-Morpholino Derivatives
- 2024
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In: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 29:11
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Journal article (peer-reviewed)abstract
- A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.
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| 2. |
- Díaz-Holguin, Alejandro, et al.
(author)
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AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine-associated receptor 1
- 2024
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:32
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Journal article (peer-reviewed)abstract
- Artificial intelligence is revolutionizing protein structure prediction, providing unprecedented opportunities for drug design. To assess the potential impact on ligand discovery, we compared virtual screens using protein structures generated by the AlphaFold machine learning method and traditional homology modeling. More than 16 million compounds were docked to models of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor of unknown structure and target for treating neuropsychiatric disorders. Sets of 30 and 32 highly ranked compounds from the AlphaFold and homology model screens, respectively, were experimentally evaluated. Of these, 25 were TAAR1 agonists with potencies ranging from 12 to 0.03 mu M. The AlphaFold screen yielded a more than twofold higher hit rate (60%) than the homology model and discovered the most potent agonists. A TAAR1 agonist with a promising selectivity profile and drug-like properties showed physiological and antipsychotic-like effects in wild-type but not in TAAR1 knockout mice. These results demonstrate that AlphaFold structures can accelerate drug discovery.
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| 3. |
- Feng, Bo, et al.
(author)
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Discovery and biological evaluation of novel dual PTP1B and ACP1 inhibitors for the treatment of insulin resistance
- 2024
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In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 97
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Journal article (peer-reviewed)abstract
- In this study, a virtual screening pipeline comprising ligand-based and structure-based approaches was established and applied for the identification of dual PTP1B and ACP1 inhibitors. As a result, a series of benzoic acid derivatives was discovered, and compound H3 and S6 demonstrated PTP1B and ACP1 inhibitory activity, with IC50 values of 3.5 and 8.2 mu M for PTP1B, and 2.5 and 5.2 mu M for ACP1, respectively. Molecular dynamics simulations illustrated that H3 interacted with critical residues in the active site, such as Cys215 and Arg221 for PTP1B, and Cys17 and Arg18 for ACP1. Enzymatic kinetic research indicated that identified inhibitors competitively inhibited PTP1B and ACP1. Additionally, cellular assays demonstrated that H3 and S6 effectively increased glucose uptake in insulin-resistant HepG2 cells while displaying very limited cytotoxicity at their effective concentrations. In summary, H3 and S6 represent novel dual-target inhibitors for PTP1B and ACP1, warranting further investigation as potential agents for the treatment of diabetes.
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| 4. |
- Hu, Huabin, et al.
(author)
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A machine learning and live-cell imaging tool kit uncovers small molecules induced phospholipidosis
- 2023
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In: Cell Chemical Biology. - : Elsevier. - 2451-9456 .- 2451-9448. ; 30:12, s. 1634-1651.e6
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Journal article (peer-reviewed)abstract
- Drug-induced phospholipidosis (DIPL), characterized by excessive accumulation of phospholipids in lysosomes, can lead to clinical adverse effects. It may also alter phenotypic responses in functional studies using chemical probes. Therefore, robust methods are needed to predict and quantify phospholipidosis (PL) early in drug discovery and in chemical probe characterization. Here, we present a versatile high-content live-cell imaging approach, which was used to evaluate a chemogenomic and a lysosomal modulation library. We trained and evaluated several machine learning models using the most comprehensive set of publicly available compounds and interpreted the best model using SHapley Additive exPlanations (SHAP). Analysis of high-quality chemical probes extracted from the Chemical Probes Portal using our algorithm revealed that closely related molecules, such as chemical probes and their matched negative controls can differ in their ability to induce PL, highlighting the importance of identifying PL for robust target validation in chemical biology.
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| 5. |
- Wang, Yao, et al.
(author)
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Polaronic Trions Induced by Strong Interfacial Coupling in Monolayer WSe2
- 2023
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In: Advanced Electronic Materials. - : Wiley. - 2199-160X. ; 9:2
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Journal article (peer-reviewed)abstract
- The weak dielectric screening in 2D semiconducting transition metal dichalcogenides give rise to strongly bound quasiparticles, which provides a platform to investigate the diverse excitonic phenomena and correlated physics. However, how to effectively control these quasiparticles is still a challenge for their applications in optoelectronic and valleytronic devices. Herein, by means of fabricating monolayer WSe2 and transition metal oxide (TMO) heterostructures, polaronic trion, that is a trion dressed with soft rotational optical (RO) phonons, is realized due to the strong interfacial coupling. This Fröhlich bound state of trion dramatically increases the trion binding energy (BE) from room temperature to 65 meV at 80 K in WSe2/LaAlO3 (LAO). However, the increase of the trion BE for WSe2/SrTiO3 (STO) occurs below the phase transition temperature. This work expands the possibilities of the TMDs/TMOs heterostructures and promotes the development of 2D van der Waals materials for quasiparticle-based devices.
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