Molecular Dynamics Study of MJ-33 and Derivatives Designed as cKit Kinase Inhibitors

摘要

Background and Objective: Due to the high mortality rate, cancer is still a burden to society and therefore, the development of anticancer therapies is necessary. In our lab, a quinazolinone compound (MJ-33) was synthesized and showed an inhibitory effect on several types of cancer cells. However, the direct biological target was not clarified. This study aimed to investigate possible molecular targets of MJ-33. Materials and Methods: In a computational approach, 2-step in silico screening, using molecular docking and Molecular Dynamics (MD) simulation was carried out to identify top-high affinity and most stable targets of MJ-33. MD simulations in 100 ns were performed to identify intermolecular interactions and structural insights of ligand-protein complexes. Results: MJ-33 has a strong affinity with cKit kinase. During the simulation course, the MJ33-cKit complex remained stable and no large conformational change of the protein was detected. Besides, an MJ-33 derivative (C93) was proposed as a potential cKit inhibitor. C93 may establish a complex with cKit kinase with several improvements for complex stability and intermolecular interactions, compared with those of MJ-33. Conclusion: In summary, our study suggested that cKit kinase is possibly the direct biological target of MJ-33. Based on the structural insight of the MJ33-cKit complex and MJ-33 scaffold, a rational drug design was carried out to propose a promising cKit inhibitor to be developed in the future.