Flavoxate 250mg/5ml oral solution

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is a key therapeutic target for inflammatory and neoplastic diseases such as rheumatoid arthritis (RA) and certain types of cancer. Although several inhibitors have been approved for medical use, their associated adverse effects limit their therapeutic use. Therefore, it is essential to search for new, safer inhibitors. In this work, we applied computer-aided approaches consisting of consensus molecular docking and molecular dynamics using the JAK2 structure as a filter of 3330 drugs approved by the Food and Drug Administration (FDA) retrieved from the ZINC20 database. The best predicted virtual hits were evaluated in an ex vivo STAT1,3 phosphorylation functional model in human lymphocytes induced by IL-6 stimulation. The docking-based consensus-scoring strategy allowed the selection of pitavastatin (PIT), eltrombopag (ELT), flavoxate (FLA), and empagliflozin (EMP) as potential JAK2 inhibitors. Their stability was confirmed by running independent molecular dynamics simulations of 200 ns in triplicate, which showed comparable stability with baricitib (BAR) and showed that hydrogen bonding is involved in their binding with key amino acids of the ATP-binding site. In the ex vivo evaluations, pitavastatin (0.5004 μM), eltrombopag (0.2548 μM), flavoxate (0.1536 μM), and empagliflozin (0.2548 μM) affected the phosphorylation of downstream STAT1 and STAT3 signaling molecules, similarly to tofacitinib citrate (TOF) (1.2 nM ). These results encourage further in-depth preclinical experiments aimed at exploring the additional effects of the JAK2-STAT1/3 signaling pathway.

Abstract licence: CC BY-NC-ND

The prevailing fungal infections, especially with Candida albicans are serious health concern particularly in immunocompromised patients. Considering the menace of drug resistance and tremendous mortality ratio of Candida-related infections, consequential efforts are ongoing to characterize new drug targets or agents for therapeutic intervention. As a consequence, in the present study, we targeted Rrp9 protein from Candida albicans which plays an essential role in ribosome biogenesis and it has role in the cellular response to certain drugs. Sequence analysis using BLAST protein search and 3D modeling using Discovery Studio (DS) program for Rrp9 protein prediction were carried out. The antifungal activity of few selected ligands, antimuscarinc acetylcholine receptor drugs (Dicyclomine, Solifenacin, Hydroxyzine, Promethazine and Flavoxate) on the predicted 3D model of Rrp9 protein through molecular docking studies using GOLD software was done. Our in silico analysis afforded insight information of structure and binding interactions of 3D modeling C. albicans Rrp9 protein with these selected ligands. All compounds showed good docking interaction with Rrp9 protein. The antimuscarinic, Solifenacin succinate presented better interactions with good binding energy. We suggested that these antimuscarinic drugs can be used as anti-Candidal albicans as well as antifungal agents.

Abstract licence: CC BY