Molecular docking methodology is useful in predicting comparative binding affinity of library of different ligands whose co-crystal structure in complex form is already known. However, scope of this methodology is not reliable for cross docking of different ligands due to incorrect prediction of binding pose if co-crystal structure is unknown. In the present work, we have studied the ligand polarization due to protein environment during the docking of seven ligands in envelope protein of dengue virus. We have used six kinase inhibitors which are active for dengue virus as well and a detergent molecule whose crystal structure is already known. We observed major change in docking scores due to polarization of ligands. The charges of the ligands were calculated by ab initio methods for the accuracy of our results. We observed increased hydrogen bonding due to polarization in protein environment. These results are more significant for inhibitors containing electronegative elements like chlorine and fluorine. © Springer Science+Business Media, LLC 2011.