Detailed structural investigation of Crizotinib and the exploration of its antitumor potential by DFT calculations and molecular docking

Detailed structural investigation and exploration of the potential clinical indications are necessary for the drug reevaluation of newly-approved drugs. Crizotinib is a potent and selective receptor tyrosine kinases (RTK) dual inhibitor approved for treatment of non-small cell lung carcinoma (NSCLC) by FDA. In this work, a detailed structural research of Crizotinib molecule including molecular structural optimization, Mulliken population, molecular electrostatic potential, vibrational frequencies have been performed by theoretical calculations. The chiral structure was also examined by experimental and simulated electrostatic circular dichroism (ECD) spectrum at different calculation levels. Moreover, the potential clinical indications of Crizotinib are also predicted by molecular docking based on increasing case reports in curation of various cancers. The molecular docking data supported the potential interaction of Crizotinib with various therapeutic targets. In addition to the acknowledged interactions with therapeutic target for NSCLC (C-met, ALK, NTRK), some other targets such as PD-1 and POM121 for breast and prostatic cancer, respectively, were firstly observed to be able to interact with Crizotinib, which have been confirmed by the recent clinical findings. Our research provided a probable explanation of the unique therapeutic effect of Crizotinib for breast and prostatic cancer, and also guided a way for new clinical uses for old drug such as Crizotinib.