  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.
