Abstract
In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD) simulation and binding free energy (ΔGbind) calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds) in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA), and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors.
Highlights
In spite of the progress in medicine, developing new anticancer drugs is still important because cancer still acts as a major problem of health all over the world [1]
RMSD fluctuations of the three complexes were calculated during molecular dynamic (MD) simulations, and the results are consistent with their inhibitory activities
RMSF values for each residue surrounding the ligand of the three complexes were computed during MD simulations and each RMSF is lower than 1.0 Å, which indicates that the binding pocket is stable during the MD simulations
Summary
In spite of the progress in medicine, developing new anticancer drugs is still important because cancer still acts as a major problem of health all over the world [1]. The first B-Raf kinase inhibitor (BRI) approved by the Food and Drug Administration (FDA) is Sorafenib, which is used to treat hepatocellular carcinoma and renal cell carcinoma in clinic. All the 36 imidazopyridines were docked into the binding pocket of B-Raf kthineaisme irdeacezpotpoyrrsiudcinceesssafurellys.hTohwenchinemTiacballestSr1uc(stuu2r7pe3ps5,l1ebmioelongtaicrayl activity values data). All the 36 imidazopyridines were docked into the binding pocket of B-Raf kinase receptor successfully. Acceptable reliability of the docking method for the B-Raf kinase receptor and these inhibitors. To explore the stability of the binding pocket during the MD simulations process, the rooTto-meexapnl-osrqeuatrheed fsltuacbtiuliattyionosf (tRhMe SbFi)nodfinagll tphoeckreestidduuersinagroutnhde tMheDligsaimndulaattiaon≤s5 Åprodciestsasn, cethe roowt-emreeacnal-csuqluaaterdedbyfluthcetuVatMioDnsso(RftwMaSrFe). Boeffoarlle tthhee RreMsiSdFuecsalcaurolautniodn,ththee laigvaenradgeatstaruďct5urÅes doifstthane ce wecroemcapllceuxelastwederbeycothmepVutMedDwsiothftiwn athree.laBstef1onres ttrhaejeRctMorSyFocf aMlcDulsaitmiounl,attihoensa,vaenrdagtheesntreuaccthurreessidofuethe comsuprlreoxuensdwinegrethceomligpauntdedwwasitahlingntehde tloastth1e navsetrraagjeecstotrruyctoufrMe. DThseimreuslidatuioesnsa,roaunnddththene leigacahndreasnidue surtrhoeuirnRdMinSgFthvealuliegsancodmwparseadliwgnitehdthtoe stthaertainvgersatrguectsutruesctaurreel.isTtehdeinreTsiadbulees1.aIrnoualnldthtehceolmigpalnedxeas,nd thetihreRRMMSSFFvafolur eesacohmrepsaidreude wsuitrhrotuhnedsitnagrtitnhge slitgruanctduriessloawreelristtheadnin.T0aÅbl,ew1.hiIcnhamll etahnescothmatpltehxees, thebRinMdiSnFgfpoorcekaecthisrqesuiidteusetasbulreroduunridnigngthtehMe lDigsainmduilsatlioown.er than 1.0 Å, which means that the binding pocket is quite stable during the MD simulation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
