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.

简介：免疫的主要调节因子白细胞介素 2 (IL2) 的异常表达与许多自身免疫疾病有关。目前还没有FDA批准的靶向IL2的药物，这就需要小分子抑制剂来阻断IL2及其受体相互作用。

方法：在此，我们使用当代的fragnomics 方法来设计针对IL2 的新型药物类抑制剂。简而言之，利用在 MOE（分子操作环境检查）软件套件中实施的 RECAP（逆合成组合分析程序）包来获得满足片段“三规则”标准的片段。IL2 的结合位点被分成三个较小的凹槽，并将片段对接以筛选它们对特定位点的亲和力，然后进行定点 RECAP 合成。

结果： 根据对接中观察到的对特定位点的亲和力重新组合片段，制备了 10,000 种化合物的集中文库。对接和随后对新合成化合物的分析确定了 40 条特权引线，它们与口袋的碱性残基形成氢键。使用 QSAR 模型来预测化合物的 IC50 并分析静电和疏水等高线图。发现产生的命中是适度的 IL2 抑制剂，预测的抑制活性在 5.17-4.40 nM 的范围内。进行进一步的动态模拟研究以确定抑制剂-IL2复合物的稳定性。

结论：我们的研究结果强调了新化合物作为以 IL2 过表达为特征的疾病的有价值的药理剂的潜力。