Improvement of binding pose prediction of the MR1 covalent ligands by inclusion of simple pharmacophore constraints and structural waters in the docking process.

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03694-w.