Exploring New Potential Pkcθ Inhibitors Using Pharmacophore Modeling, Molecular Docking Analysis, and Molecular Dynamics Simulations

Background: It has been reported that PKC theta plays an important role in the immune response by regulating the cellular activity of T cells and, thus, the production of immune factors such as IL-2.PKC theta protein is mainly expressed in T lymphocytes but not much in other cells and has a very good specificity. Therefore, it is very meaningful to use PKC theta protein as a novel target for immunosuppression. PKC theta is a valuable target that can be used to develop meaningful novel selective immunosuppressive agents. Methods: In this study, we constructed a 3-characteristic pharmacophoreRHAand used it to perform a virtual screening of the database. Then, we performed a molecular docking analysis of the compounds that scored high. The top five compounds with molecular docking scores were used as lead compounds, and structure-based ligand design via fragment substitution was applied to them, resulting in 20077 new compounds. We performed molecular docking analysis, binding free energy calculations, molecular dynamics simulation, and ADMET prediction on these new compounds and finally identified two compounds as new PKC theta inhibitors. Results and Discussions: Through the screening of pharmacophore, molecular design based on fragment substitution, molecular docking, we finally obtained two small molecules with higher scores than the positive control, in which the molecular docking score of P01 was -53.88 kcal/mol, and the molecular docking score of P02 was -51.20 kcal/mol, and then we performed the molecular dynamics simulation, free energy of binding calculations, and the prediction of ADMET properties for the compounds. The results showed that the ligands could form more stable complexes with the proteins, the binding free energy calculations of the ligand molecules were better than the positive control, all of them had good ADMET properties, and the compounds all had good drug similarity. Conclusion: Our results provided 2 new ligands that could serve as lead compounds for new PKC theta inhibitors in the future.