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Abstract：
The major histocompatibility complex (MHC) class I-related molecule, MR1, is a key component of the immune system, presenting antigens to T-cell receptors (TCRs) and modulating the immune response against various antigens. MR1 possesses a compact ligand-binding pocket despite its ability to interact with ligands that can have either agonistic or antagonistic effects on the immune system. Agonistic ligands can stimulate the immune response, while antagonistic ligands do not elicit an immune response. In most cases, ligand binding to MR1 is mediated through a covalent bond with Lys43. However, recent studies have suggested that a variety of small molecules can interact with the MR1-binding site. In this study, we have used several approaches to improve the binding pose prediction of covalent ligands to MR1, including docking in mutated receptors, and imposing simple pharmacophore constraints and structural water molecules. The careful assignment of pharmacophore constraints and inclusion of structural water molecules in the challenging docking process of covalent docking improved the binding pose prediction and virtual screening performance. In a retrospective virtual screening, the proposed approach exhibited EF1% and EF2% values of 7.4 and 5.5, respectively. Conversely, when using the mutated receptor, both EF1% and EF2% were recorded as 0 for the conventional docking method. The performance of the pharmacophore constraints was also evaluated on other covalent docking cases, and compared to previously reported results for common covalent docking methods. The proposed approach achieved an average RMSD of 2.55, while AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE exhibited average RMSD values of 3.0, 2.93, 3.04, 4.93, 2.44, and 3.36, respectively. Our results demonstrate that the inclusion of simple pharmacophore constraints and structural waters can improve the prediction of binding poses of covalent ligands to MR1, which can aid in the discovery of novel immunotherapeutic agents.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13205-023-03694-w.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s13205-023-03694-w.
摘要：
主要组织相容性复合体（MHC）I类相关分子，MR1是免疫系统的重要组成部分,将抗原呈递至T细胞受体(TCR)并调节针对各种抗原的免疫应答。MR1具有紧密的配体结合口袋,尽管其能够与可对免疫系统具有激动或拮抗作用的配体相互作用。激动剂配体可以刺激免疫反应，而拮抗配体不引起免疫反应。在大多数情况下,配体与MR1的结合是通过与Lys43的共价键介导的。然而,最近的研究表明，多种小分子可以与MR1结合位点相互作用。在这项研究中,我们已经使用了几种方法来改善共价配体与MR1的结合状态预测，包括在突变受体中对接，施加简单的药效基团约束和结构水分子。在具有挑战性的共价对接对接过程中仔细分配药效团约束和包含结构水分子改善了结合姿态预测和虚拟筛选性能。在回顾性虚拟筛查中，建议的方法显示EF1％和EF2％值分别为7.4和5.5。相反，当使用突变的受体时，常规对接方法的EF1%和EF2%均记录为0。在其他共价对接案例中还评估了药效团约束的性能，并与以前报道的常见共价对接方法的结果进行比较。所提出的方法实现了2.55的平均RMSD，而AutoDock4、CovDock、FITTED,黄金,ICM-Pro,和MOE的平均RMSD值分别为3.0、2.93、3.04、4.93、2.44和3.36。我们的结果表明，包含简单的药效团约束和结构水可以改善共价配体与MR1的结合姿势的预测，这可以帮助发现新型免疫治疗剂。
■在线版本包含补充材料，可在10.1007/s13205-023-03694-w获得。
■在线版本包含补充材料，可在10.1007/s13205-023-03694-w获得。
