Virtual discovery of a hetero-cyclic compound from the Universal Natural Product Database (UNPD36) as a potential inhibitor of interleukin-33: molecular docking and dynamic simulations.

Interleukin (IL)-33 is a cytokine implicated in several inflammatory and autoimmune diseases. Upon binding to its receptor ST2, IL-33 activates allergic inflammatory responses. To block this protein-protein interaction with a potential anti-allergic agent, we screened Universal Natural Product Database (UNPD) using a combined approach of molecular docking and dynamic simulations. Six hundred compounds with high gastrointestinal absorption properties from the UNPD were retrieved and subjected to molecular docking using Autodock Vina, out of which four hetero-cyclic compounds (UNPD36, UNPD2045, UNPD8905, UNPD122514) were found to have binding energy score of < -7.0 Kcal/mol. Further analysis from 100 ns MD simulation of the best hit (UNPD36) revealed that IL-33_UNPD36 complex reached average stability at RMSD of 2.7 Å, and residues involved in the interaction showed lower fluctuations compared to the residues at the β4-β5 and β11-β12 loop region. Further molecular docking using Autodock 4.2 was carried out to determine the binding orientation of UNPD36. Using GROMACS, additional 50 ns MD simulations and MM-PBSA calculation were performed on this complex. Finally, chemoinformatic studies revealed that the UNPD36 had drug-like and pharmacokinetic profiles as well as potentials for oral and topical applications, in addition to good safety profile. Thus, it was concluded that a hetero-cyclic compound with chromone moiety (UNPD36) had a good and stable binding mode to serve as potential inhibitor of IL-33 and/or may provide a scaffold for further optimization toward the design of more potent inhibitors for application in the treatment of respiratory allergies.Communicated by Ramaswamy H. Sarma.