Docking and mutagenesis studies lead to improved inhibitor development of ML355 for human platelet 12-lipoxygenase
| Autor: | Theodore R. Holman, Melinee D’silva, Harman S. Brah, Wan-Chen Tsai, Jennyfer Tena, Ansari Mukhtar Aleem, Chakrapani Kalyanaraman, Mirella Rivera-Velazquez, Sarvind Tripathi, Matthew P. Jacobson, Jerry L. Nadler |
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| Rok vydání: | 2021 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Arachidonate 12-Lipoxygenase Biochemistry Structure-Activity Relationship Lipoxygenase chemistry.chemical_compound Drug Development Drug Discovery Humans Potency Lipoxygenase Inhibitors Platelet activation Molecular Biology ADME Sulfonamides Dose-Response Relationship Drug Molecular Structure biology Chemistry Drug discovery Organic Chemistry Active site Molecular Docking Simulation Benzothiazole Docking (molecular) biology.protein Biophysics Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 46:116347 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2021.116347 |
| Popis: | Human platelet 12-(S)-Lipoxygenase (12-LOX) is a fatty acid metabolizing oxygenase that plays an important role in platelet activation and cardiometabolic disease. ML355 is a specific 12-LOX inhibitor that has been shown to decrease thrombosis without prolonging hemostasis and protect human pancreatic islets from inflammatory injury. It has an amenable drug-like scaffold with nM potency and encouraging ADME and PK profiles, but its binding mode to the active site of 12-LOX remains unclear. In the current work, we combined computational modeling and experimental mutagenesis to propose a model in which ML355 conforms to the "U" shape of the 12-LOX active site, with the phenyl linker region wrapping around L407. The benzothiazole of ML355 extends into the bottom of the active site cavity, pointing towards residues A417 and V418. However, reducing the active site depth alone did not affect ML355 potency. In order to lower the potency of ML355, the cavity needed to be reduced in both length and width. In addition, H596 appears to position ML355 in the active site through an interaction with the 2-methoxy phenol moiety of ML355. Combined, this binding model suggested that the benzothiazole of ML355 could be enlarged. Therefore, a naphthyl-benzothiazole derivative of ML355, Lox12Slug001, was synthesized and shown to have 7.2-fold greater potency than ML355. This greater potency is proposed to be due to additional van der Waals interactions and pi-pi stacking with F414 and F352. Lox12Slug001 was also shown to be highly selective against 12-LOX relative to the other LOX isozymes and more importantly, it showed activity in rescuing human islets exposed to inflammatory cytokines with comparable potency to ML355. Further studies are currently being pursued to derivatize ML355 in order to optimize the additional space in the active site, while maintaining acceptable drug-like properties. |
| Databáze: | OpenAIRE |
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