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
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.