In silico discovery of small-molecule K-Ras inhibitor

Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequentlyobserved in human cancers, making them promising anticancer drug targets [۱]. Mutation of the protooncogeneK-Ras is one of the most common molecular mechanisms in non-small cell lung cancer. Manydrugs for treating lung cancer have been developed, however, due to clinical observed K-Ras mutations,corresponding chemotherapy and targeted therapy for such mutation are not efficient enough. In thisstudy, on the basis of the crystal structure of ۴DSU, GDP-bound K-RasG۱۲D mutant [۲], ۲۵ structuralanalogues of vismodegib, a hedgehog pathway inhibitor [۳] were rationally designed. The designing ofthese compounds was based on the structure of ۴DSU protein, and the related groups were replaced bybioisosteres to improve the affinity and selectivity.Performing molecular docking:Using PyRx, Autodock, Discovery Studio, UCSF Chimera and PyMol, make the desired changes (suchas adding charge, converting protein and ligands to Pdbqt, adding hydrogen, removing extra molecules,etc.) on the protein and ligands. The desired docking on the protein and ligands was done, and analyzethe obtained results using the Ligplot, Protein Ligand Interaction profiler, and PDBSum programs.Docking analysis showed that the VIS۱۷ can effectively bind (ΔGbind= -۹.۴ Kcal/mol) to the key aminoacids of the enzyme active site and form a hydrogen bond with the LYS ۸۹A.The structure andFunctional groups of VIS۱۷ was shown below.In conclusion, our studies in finding novel potent compound (VIS۱۷) with confirmed mechanismshowed great potential for further optimisation and other medicinal chemistry relevant studies.

کلیدواژه ها:

K-Ras ، ۴DSU ، vismodegib ، docking ، anticancer drug