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2,223 results on '"Liu, Yongfeng"'

5. Docking for EP4R antagonists active against inflammatory pain.

Author

Gahbauer, Stefan, DeLeon, Chelsea, Braz, Joao, Craik, Veronica, Kang, Hye, Wan, Xiaobo, Huang, Xi-Ping, Billesbølle, Christian, Liu, Yongfeng, Che, Tao, Deshpande, Ishan, Fink, Elissa, Kondratov, Ivan, Moroz, Yurii, Roth, Bryan, Basbaum, Allan, Shoichet, Brian, Jewell, Madison, and Irwin, John

Subjects
Humans, Mice, Animals, Dinoprostone, Receptors, Prostaglandin, Phagocytosis, Anti-Inflammatory Agents, Pain, Anti-Inflammatory Agents, Non-Steroidal
Abstract

The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.

Published
2023

20. Determination of lactose in milk by high performance liquid chromatography-evaporative light scattering detector with RCM-monosaccharide Ca2+ column

Author

ZHU Xiaopeng, FU Shangchen, HAO Guo, NIU Pengfei, and LIU Yongfeng

Subjects
cow's milk, lactose, rcm-monosaccharide ca2+ column, high performance liquid chromatography, evaporative light scattering detector, Food processing and manufacture, TP368-456
Abstract

Objective: To achieve rapid detection of lactose content in milk, a new method for the determination of lactose in milk based on RCM-monosaccharide Ca2+ column and high-performance liquid chromatography has been established. Methods: Milk was precipitated with protein in a 0.2 g/mL trichloroacetic acid solution, and the resulting filtrate was diluted 100 times and filtered with a membrane before entering a high-performance liquid chromatography system. It was separated by an RCM-monosaccharide Ca2+ column and detected by an evaporative light scattering detector. Results: The results showed that lactose had a good correlation between peak area and concentration in the linear range （20~100 mg/L）, with an R2 of 0.999 8. When the lactose spiking levels were 15, 40, and 80 mg/g, the recovery range was between 90.96% and 98.23%, the detection limit was 3.6 μg/g, and the quantitative limit was 12 μg/g, the lactose concentration was determined within 6 minutes. 11 commercial milk samples were measured by this method, and the results were consistent with the national standard method. Conclusion: The precision, repeatability, and recovery rate of this method met relevant regulations, and the detection results were accurate and time-consuming. It is suitable for rapid detection of lactose content in milk.

Published
2023
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50. Structures of the σ2 receptor enable docking for bioactive ligand discovery

Author

Alon, Assaf, Lyu, Jiankun, Braz, Joao M, Tummino, Tia A, Craik, Veronica, O’Meara, Matthew J, Webb, Chase M, Radchenko, Dmytro S, Moroz, Yurii S, Huang, Xi-Ping, Liu, Yongfeng, Roth, Bryan L, Irwin, John J, Basbaum, Allan I, Shoichet, Brian K, and Kruse, Andrew C

Subjects
Peripheral Neuropathy, Pain Research, Chronic Pain, Neurosciences, Neurodegenerative, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Animals, Ligands, Mice, Neuralgia, Receptors, sigma, Structure-Activity Relationship, General Science & Technology
Abstract

The σ2 receptor has attracted intense interest in cancer imaging1, psychiatric disease2, neuropathic pain3-5 and other areas of biology6,7. Here we determined the crystal structure of this receptor in complex with the clinical candidate roluperidone2 and the tool compound PB288. These structures templated a large-scale docking screen of 490 million virtual molecules, of which 484 compounds were synthesized and tested. We identified 127 new chemotypes with affinities superior to 1 μM, 31 of which had affinities superior to 50 nM. The hit rate fell smoothly and monotonically with docking score. We optimized three hits for potency and selectivity, and achieved affinities that ranged from 3 to 48 nM, with up to 250-fold selectivity versus the σ1 receptor. Crystal structures of two ligands bound to the σ2 receptor confirmed the docked poses. To investigate the contribution of the σ2 receptor in pain, two potent σ2-selective ligands and one potent σ1/σ2 non-selective ligand were tested for efficacy in a mouse model of neuropathic pain. All three ligands showed time-dependent decreases in mechanical hypersensitivity in the spared nerve injury model9, suggesting that the σ2 receptor has a role in nociception. This study illustrates the opportunities for rapid discovery of in vivo probes through structure-based screens of ultra large libraries, enabling study of underexplored areas of biology.

Published
2021

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