Department of Chemistry, The University of Nebraska at Omaha, 6001 Dodge Street, Omaha, NE 68182, USA.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Buraidah 51542, Saudi Arabia.
Int J Mol Sci. 2023 Mar 23;24(7):6023. doi: 10.3390/ijms24076023.
The Janus kinases (JAKs) are a family of non-receptor cytosolic protein kinases critical for immune signaling. Many covalently bound ligands of JAK3 inhibitors have been reported. To help design selective JAK inhibitors, in this paper, we used five model proteins to study the subtype selectivity of and the mutational effects on inhibitor binding. We also compared the Covalent Dock programs from the Schrodinger software suite and the MOE software suite to determine which method to use for the drug design of covalent inhibitors. Our results showed that the docking affinity from 4Z16 (JAK3 wild-type model), 4E4N (JAK1), 4D1S (JAK2), and 7UYT (TYK2) from the Schrödinger software suite agreed well with the experimentally derived binding free energies with small predicted mean errors. However, the data from the mutant 5TTV model using the Schrödinger software suite yielded relatively large mean errors, whereas the MOE Covalent Dock program gave small mean errors in both the wild-type and mutant models for our model proteins. The docking data revealed that Leu905 of JAK3 and the hydrophobic residue at the same position in different subtypes (Leu959 of JAK1, Leu932 of JAK2, and Val981 of TYK2) is important for ligand binding to the JAK proteins. Arg911 and Asp912 of JAK3, Asp939 of JAK2, and Asp988 of TYK2 can be used for selective binding over JAK1, which contains Lys965 and Glu966 at the respective positions. Asp1021, Asp1039, and Asp1042 can be utilized for JAK1-selective ligand design, whereas Arg901 and Val981 may help guide TYK2-selective molecule design.
Janus 激酶（JAKs）是一类非受体胞质蛋白激酶，对免疫信号至关重要。已经报道了许多共价结合的 JAK3 抑制剂配体。为了帮助设计选择性 JAK 抑制剂，在本文中，我们使用了五个模型蛋白来研究抑制剂结合的亚型选择性和突变效应对抑制剂结合的影响。我们还比较了 Schrödinger 软件套件和 MOE 软件套件中的 Covalent Dock 程序，以确定哪种方法用于共价抑制剂的药物设计。我们的结果表明，来自 Schrödinger 软件套件的 4Z16（JAK3 野生型模型）、4E4N（JAK1）、4D1S（JAK2）和 7UYT（TYK2）的对接亲和力与实验得出的结合自由能吻合良好，预测平均误差较小。然而，来自 Schrödinger 软件套件的突变体 5TTV 模型的数据产生了相对较大的平均误差，而 MOE Covalent Dock 程序在我们的模型蛋白的野生型和突变型模型中都给出了较小的平均误差。对接数据表明，JAK3 的 Leu905 及其在不同亚型中的相同位置的疏水性残基（JAK1 的 Leu959、JAK2 的 Leu932 和 TYK2 的 Val981）对配体与 JAK 蛋白的结合很重要。JAK3 的 Arg911 和 Asp912、JAK2 的 Asp939 和 TYK2 的 Asp988 可用于与 JAK1 选择性结合，而 JAK1 相应位置含有 Lys965 和 Glu966。Asp1021、Asp1039 和 Asp1042 可用于设计 JAK1 选择性配体，而 Arg901 和 Val981 可能有助于指导 TYK2 选择性分子设计。
