Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi–alkyl, and pi–sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

中文翻译：

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用于治疗自身免疫性疾病的 Janus 激酶的托法替尼和佩菲替尼抑制剂：一种量子生物化学方法

自身免疫性炎症疾病，例如类风湿性关节炎（RA）和溃疡性结肠炎，与细胞因子的不受控制的产生有关，导致这些疾病的明显炎症反应。他们的治疗目前集中在抑制细胞因子受体，例如 Janus 激酶 (JAK) 蛋白家族。托法替尼和佩菲替尼是最近被批准用于治疗类风湿性关节炎的 JAK 抑制剂。在本研究中，通过量子生物化学进行了深入分析，以了解JAK1与托法替尼或培菲替尼形成的复合物中涉及的相互作用。计算分析为托法替尼或培菲替尼与 JAK1 之间的结合机制提供了新的见解。还鉴定并报告了支持该复合物的必需氨基酸残基。此外，我们还报告了新的相互作用，例如范德华；氢键;以及烷基、π-烷基和π-硫力，可稳定络合物。计算结果显示，根据相互作用能量，与托法替尼相比，佩菲替尼对 JAK1 具有相似的亲和力。