Identification of potential inhibitor targeting KRAS mutation in Papillary Thyroid Carcinoma through molecular docking and dynamic simulation analysis

Thyroid cancer is a predominant form of endocrine malignancy, which destabilizes the metabolic rate of the body. The rapid increase in the incidence rate of thyroid cancer in recent years has aroused great concern to be investigated and diagnosed at an early stage. This study aimed to analyze the pathogenic mutations in thyroid cancer to identify their potential inhibitors for therapeutic targets. RAS genes are the most common oncogenes, which encode proteins that play an essential role in cell signaling and have been frequently mutated in different cancer types. The mutation in these genes causes abnormal cell growth and fails to respond to death signals. In this study, we identified the most significant mutations in the RAS genes; thus, the highly pathogenic mutations were curated from thyroid cancer patients and analyzed for their pathogenicity effect. The physicochemical analysis predicted mutation in wild-type KRAS protein had adapted negative charge on single base substitution of G12D that may easily cause loss of interactions and result in critical differences in the structure and function of the protein. Furthermore, the native KRAS protein was mutated and screened against a library of druggable compounds from the ZINC drug repository. The molecular docking analysis revealed that G12D mutant KRAS protein form best-docked complex with Naldemedine with the highest binding affinity. The dynamic simulation results further justified the stability of Naldemedine as a potential inhibitor with high efficiency in MMPBSA value of -45.4867 kcal/mol of being treated as a potential drug for papillary thyroid carcinoma. Further in vivo and in vitro validation of Naldemedine and its efficiency as a drug for the targeted pathogenic KRAS mutation is required.