Author: Li, Jingjing ; Xia, Kaijiang ; Li, Zhanhui ; He, Sudan ; Hao, Yongjin ; Shu, Chang ; Ma, Haikuo ; Ji, Yuting ; Tian, Sheng ; Wu, Shuwei ; Yang, Chengkui ; Zhang, Xiaohu

Receptor-interacting protein kinase-1 (RIPK1) is involved in the necroptosis pathway, which regulates inflammatory signaling and cell death in a variety of diseases, including inflammatory and neurodegenerative disorders. We identified a novel hit compound 36 by a cell-based screening assay (anti-necroptosis EC₅₀ = 58 nM). Starting from compound 36, we designed a series of scaffolds to improve anti-necroptosis activity, physicochemical properties and metabolic stability. The isothiazolo[5,4-b]pyridine backbone proved to be a promising scaffold which provided a number of potent necroptosis inhibitors. Compound 56, for example, effectively blocked necroptosis in both human and mouse cells (EC₅₀ = 1-5 nM). A binding assay showed that compound 56 potently binds to RIPK1 (K_d = 13 nM), but not RIPK3 (K_d > 10,000 nM). Kinase functional assay (ADP-Glo) confirmed that compound 56 inhibits RIPK1 phosphorylation with an IC₅₀ at 5.8 nM. Importantly, compound 56 displayed excellent cross-species liver microsomal metabolic stability (t1/2 > 90 min). Furthermore, compound 56 exhibited favorable in vitro safety profiles in hERG and CYP assays. Finally, pre-treatment with 56 significantly reduced hypothermia and lethal shock in the systemic inflammatory response syndrome mice model. Taken together, compound 56 represented a promising prototype for the development of therapeutic agent to treat inflammation-related diseases.

Molecules

Docking and Molecular Dynamic Investigations of Phenylspirodrimanes as Cannabinoid Receptor-2 Agonists

Article

Author: Omar, Abdelsattar M. ; Aljahdali, Anfal S. ; Ibrahim, Sabrin R. M. ; Safo, Martin K. ; Mohamed, Gamal A.

Cannabinoid receptor ligands are renowned as being therapeutically crucial for treating diverse health disorders. Phenylspirodrimanes are meroterpenoids with unique and varied structural scaffolds, which are mainly reported from the Stachybotrys genus and display an array of bioactivities. In this work, 114 phenylspirodrimanes reported from Stachybotrys chartarum were screened for their CB2 agonistic potential using docking and molecular dynamic simulation studies. Compound 56 revealed the highest docking score (−11.222 kcal/mol) compared to E3R_6KPF (native agonist, gscore value −12.12 kcal/mol). The molecular docking and molecular simulation results suggest that compound 56 binds to the putative binding site in the CB2 receptor with good affinity involving key interacting amino acid residues similar to that of the native ligands, E3R. The molecular interactions displayed π–π stacking with Phe183 and hydrogen bond interactions with Thr114, Leu182, and Ser285. These findings identified the structural features of these metabolites that might lead to the design of selective novel ligands for CB2 receptors. Additionally, phenylspirodrimanes should be further investigated for their potential as a CB2 ligand.

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Indication	Highest Phase	Country/Location	Organization	Date
Psoriasis	Preclinical	United States	Protheragen, Inc.	-

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