Molecular dynamics simulation, free energy calculation and structure-based 3D-QSAR studies of B-RAF kinase inhibitors

Ying Yang, Jin Qin, Huanxiang Liu, Xiaojun Yao

Research output: Contribution to journalArticlepeer-review

80 Citations (Scopus)


V600EB-RAF kinase is the most frequent onco-genic protein kinase mutation in melanoma and is a promising target to treat malignant melanoma. In this work, a molecular modeling study combining QM-polarized ligand docking, molecular dynamics, free energy calculation, and three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed on a series of pyridoimidazolone compounds as the inhibitors of V600EB-RAF kinase to understand the binding mode between the inhibitors and V600EB-RAF kinase and the structural requirement for the inhibiting activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by QM-polarized ligand docking strategy. The obtained models have a good predictive ability in both internal and external validation. Furthermore, molecular dynamics simulation and free energy calculations were employed to determine the detailed binding process and to compare the binding mode of the inhibitors with different activities. The binding free energies calculated by MM/PBSA gave a good correlation with the experimental biological activity. The decomposition of free energies by MM/GBSA indicates the van der Waals interaction is the major driving force for the interaction between the inhibitors and V600EB-RAF kinase. The hydrogen bond interactions between the inhibitors with Glu501 and Asp594 of the V600EB-RAF kinase help to stabilize the DFG-out conformation. The results from this study can provide some insights into the development of novel potent V600EB-RAF kinase inhibitors.

Original languageEnglish
Pages (from-to)680-692
Number of pages13
JournalJournal of Chemical Information and Modeling
Issue number3
Publication statusPublished - 28 Mar 2011
Externally publishedYes


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