In silico computational drug discovery: a Monte Carlo approach for developing a novel JAK3 inhibitors

Inhibition of Janus kinase 3 (JAK3), a member of the JAK family of tyrosine kinases, remains an essential area of research for developing treatments for autoimmune diseases, particularly cancer and rheumatoid arthritis. The recent discovery of a new JAK3 protein, PDB ID: 4Z16, offers exciting possibilities for developing inhibitors capable of forming a covalent bond with the Cys909 residue, thereby contributing to JAK3 inhibition. A powerful prediction model was constructed and validated using Monte Carlo methods, employing various internal and external techniques. This approach resulted in the prediction of eleven new molecules, which were subsequently filtered to identify six compounds exhibiting potent pIC₅₀ values. These candidates were then subjected to ADMET analysis, molecular docking (including reversible-reversible docking with tofacitinib, an FDA-approved drug, and reversible-irreversible docking for the newly designed compounds), molecular dynamics (MD) analysis for 300 ns, and calculation of free binding energy. The results suggested that these compounds hold promise as JAK3 inhibitors. In summary, the new compounds have exhibited favorable outcomes compared to other compounds across various modeling approaches. The collective findings from these investigations provide valuable insights into the potential therapeutic applications of covalent JAK3 inhibitors, offering a promising direction for the development of novel treatments for autoimmune disorders.Communicated by Ramaswamy H. Sarma.