andrographolide and Osteoporosis

A pre-trained self-attentive message passing neural network (P-SAMPNN) model was developed based on our anti-osteoclastogenesis dataset for virtual screening purpose. Validation processes proved that P-SAMPNN model was significantly superior to the other base line models. A commercially available natural product library was virtually screened by the P-SAMPNN model and resulted in confirmed 5 hits from 10 selected virtual hits. Among the confirmed hits, compounds AP-123/40765213 and AE-562/43462182 are the nanomolar inhibitors against osteoclastogenesis with a new scaffold. Further studies indicate that AP-123/40765213 and AE-562/43462182 significantly suppress the mRNA expression of RANK and downregulate the expressions of osteoclasts-related genes Ctsk, Nfatc1, and Tracp. Our work demonstrated that P-SAMPNN method can guide phenotype-based drug discovery.

Topics: Animals; Biological Products; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Mice; Mice, Inbred C57BL; Molecular Structure; Osteogenesis; Osteoporosis; Structure-Activity Relationship

In this work, we found that 14-deoxy-11,12-didehydroandrographolide (2), a derivative of andrographolide (AP, 1), had greatly reduced cytotoxicity compared with AP and exhibited moderate anti-osteoclastogenesis activity. Thirty compounds were synthesized by introducing anti-osteoporosis chemotypes at C-19 of 2. Six of them exhibited stronger inhibition of osteoclastogenesis than AP. Of note, compound 12g displayed the most potent activity with IC

Topics: Animals; Bone Resorption; Cell Differentiation; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred C57BL; Molecular Structure; Osteoclasts; Osteogenesis; Osteoporosis; RAW 264.7 Cells; Structure-Activity Relationship