The three dimensional structure of human extracellular signal-regulated kinase 1 (hERK1) was modeled and refined using homology modeling and molecular dynamics simulation. The model was assessed by profile-3D and procheck methods, which confirmed that the obtained model was reliable. Two inhibitors were docked into the refined structure by the molecular docking programs, Affinity and CDOCKER. The results show that the two inhibitors share the similar binding pattern, which interact with the residues K36 and Q87 by hydrogen bonds. Their different substituent groups lead to the different affinities with hERK1. The reconstitution of the known inhibitor, on the basis of docking result, produces a new inhibitor, which binds to hERK1 more strongly, reserves the hydrogen bonds with K36 and Q87 at the same time to form four hydrogen bonds with the residues D93, K96 and S135, significantly increasing the interaction with hERK1. The docking energies of Affinity and CDOCKER significantly decrease, even the binding free energy of MM-PBSA decreases to be the negative value. All the energy changes show the raise of inhibiting capacity. This work provided the theoretical guidance for the inhibitor design of hERK1 and the development of the new drug for the related diseases.

Key words: hERK1, homology modeling, molecular dynamics, molecular docking, inhibitors