Site-directed Fragnomics and MD Simulations Approaches to Identify Interleukin-2 Inhibitors

Abstract

Introduction: The aberrant expression of Interleukin-2 (IL2), the chief regulator of immunity, is associated with many auto-immune diseases. At present, there is no FDA approved drug targeting IL2, which puts forth the need for small molecular inhibitors to block IL2 and its receptor interaction. Methodology: Herein, we used the contemporary fragnomics approach to design novel drug-like inhibitors targeting IL2. Briefly, the RECAP (Retrosynthetic Combinatorial Analysis Procedure) package implemented in MOE (Molecular Operating Environment check) software suite was utilised to obtain fragments fulfilling the ‘rule of three’ criteria for fragments. The binding site of IL2 was divided into three smaller grooves, and the fragments were docked to screen their affinity for a particular site, followed by site-directed RECAP synthesis. Results: A focused library of 10,000 compounds was prepared by re-combining the fragments according to their affinity for a particular site as observed in docking. Docking and subsequent analysis of newly synthesised compounds identified 40 privileged leads, presenting hydrogen bonding with basic residues of the pocket. A QSAR model was implied to predict the IC50 of the compounds and to analyse the electrostatic and hydrophobic contour maps. The resulting hits were found to be modest IL2 inhibitors with predicted inhibitory activity in the range of 5.17-4.40 nM. Further Dynamic simulation studies were carried out to determine the stability of the inhibitor-IL2 complex. Conclusion: Our findings underline the potential of the novel compounds as valuable pharmacological agents in diseases characterised by IL2 overexpression.