c-Yes is a member of Src tyrosine kinase family and it is over expressed in human colorectal cancer cells. c-Yes tyrosine kinase is an attractive target due to its inhibition controls colon tumorigenesis, metastasis and angiogenesis. High throughput virtual screening and docking methods were employed to identify novel inhibitors based on the three dimensional structure of c-Yes. Kinase domain of c-Yes is modelled with reference to the crystal structure available for Src kinase structure and simulated for 100 ns to obtain ensembles with distinct conformation of the active site. Seven ensembles obtained from molecular dynamics (MD) trajectory and one homology model were used to screen library of the 2 million Enamine HTS compounds. A library of 159 Src kinase inhibitors and 6319 associated decoys is used for validation. Based on the score values, 25 compounds were shortlisted and reported as novel inhibitors of c-Yes kinase for further development of potent drugs to treat colorectal cancer. © 2014 Springer International Publishing Switzerland.