In silico Identification of tipifarnib-like compounds by structure-based pharmacophore, virtual screening and molecular docking against K-Ras post-translation in colorectal cancer

TL;DR

This study employed structure-based pharmacophore modeling, virtual screening, and molecular docking to identify potential tipifarnib-like farnesyltransferase inhibitors targeting KRAS mutations in colorectal cancer.

Contribution

It introduces a novel in silico pipeline combining pharmacophore modeling and docking to discover new farnesyltransferase inhibitors for colorectal cancer treatment.

Findings

299 molecules screened from chemical databases

Four compounds identified as potential inhibitors

Validated potential inhibitors for further biological testing

Abstract

Colorectal cancer is a public health problem.Approximately 30 to 50 \% of colorectal tumors are caused by mutations in the KRAS gene.These mutations induce uncontrolled proliferation.To date,There is no approved effective treatment for the mutated KRAS oncogene.Farnesyltransferase (FTI) inhibitors are considered a therapeutic target against the mutated KRAS oncogene.Tipifarnib is a farnesyltransferase inhibitor that was analyzed in a Phase II trial.In the present study, the three-dimensional structure of farnesyltransferase complexed with tipifarnib [1SA4] was used as a basis to exploit the characteristics of tipifarnib.A pharmacophore model was generated based on the structure using the Asinex (Gold and Platinum Collections) database.A total of 299 molecules were obtained after screening.The 299 molecules were anchored to the tipifarnib binding site in the farnesyltransferase crystal structure for docking analysis.During the molecular docking process, the pharmacophore that was modeled, and was used as a constraint to eliminate the molecules that do not satisfy the pharmacophore.Finally, four Hits identified as farnesyltransferase inhibitors for biological tests. Keywords: colorectal cancer, structure-based pharmacophore, molecular docking, KRAS, farnesyltransferase inhibitors, Virtual Screening.