Upregulation of store-operated Ca²⁺ influx via ORAI1, an integral component of the CRAC channel, is responsible for abnormal cytokine release in active rheumatoid arthritis, and therefore ORAI1 has been proposed as an attractive molecular target. In this study, we attempted to predict the mechanical insights of ORAI1 inhibitors through pharmacophore modelling, 3D-QSAR, molecular docking and free energy analysis. Various hypotheses of pharmacophores were generated and from that, a pharmacophore hypothesis with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic rings (AADRR) resulted in a statistically significant 3D-QSAR model (r² = 0.84 and q² = 0.74). We believe that the obtained statistical model is a reliable QSAR model for the diverse dataset of inhibitors against the IL-2 production assay. The visualization of contours in active and inactive compounds generated from the 3D-QSAR models and molecular docking studies revealed major interaction with GLN108, HIS113 and ASP114, and interestingly, these residues are located near the Ca²⁺ selectivity filter region. Free energy binding analysis revealed that Coulomb energy, van der Waals energy and non-polar solvation terms are more favourable for ligand binding. Thus, the present study provides the physical and chemical requirements for the development of novel ORAI1 inhibitors with improved biological activity.

经由ORAI1（CRAC通道的组成部分）的储库操作的Ca ^2+内流上调是导致活动性类风湿关节炎中异常细胞因子释放的原因，因此ORAI1已被提出作为有吸引力的分子靶标。在这项研究中，我们试图通过药效基团建模，3D-QSAR，分子对接和自由能分析来预测ORAI1抑制剂的力学见解。产生了多种药效基团假设，并由此得出了具有两个氢键受体，一个氢键供体和两个芳环（AADRR）的药效基团假设，产生了具有统计学意义的3D-QSAR模型（r ² = 0.84和q ²= 0.74）。我们相信，所获得的统计模型是针对IL-2生产测定的各种抑制剂数据集的可靠QSAR模型。由3D-QSAR模型和分子对接研究生成的活性和非活性化合物轮廓的可视化显示了与GLN108，HIS113和ASP114的主要相互作用，有趣的是，这些残基位于Ca ²⁺选择性过滤区域附近。自由能结合分析表明，库仑能，范德华能和非极性溶剂化项更有利于配体结合。因此，本研究为开发具有改善的生物活性的新型ORAI1抑制剂提供了物理和化学要求。