J Chem Inf Model - Unbinding pathways of GW4064 from human farnesoid X receptor as revealed by molecular dynamics simulations.

Tópicos

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Resumo

Farnesoid X receptor (FXR, NR1H4) is a member of a nuclear receptor superfamily, which plays important roles in bile acid homeostasis, lipoprotein and glucose metabolism, and hepatic regeneration. GW4064 is a potent and selective FXR agonist and has become a tool compound to probe the physiological functions of FXR. Until now, the mechanism of GW4064 entering and leaving the FXR pocket is still poorly understood. Here, we report a computational study of GW4064 unbinding pathways from FXR by using several molecular dynamics (MD) simulation techniques. Based on the crystal structure of FXR in complex with GW4064, conventional MD was first used to refine the binding and check the stability of GW4064 in the FXR pocket. Random acceleration MD simulations were then performed to explore the possible unbinding pathways of GW4064 from FXR. Four main pathway clusters were found, among which three subpathways, namely Paths 2A, 2B, and 1B, were observed most frequently. Multiple steered MD simulations were further employed to estimate the maximum rupture force and the sum of the forces and to characterize the intermediate states of the ligand unbinding process. By comparing the average force profiles and structural changes, Paths 2A and 2B were identified to be the most favorable unbinding pathways. The former is located between the H1-H2 loop and the H5-H6 loop, and the latter is located in the cleft formed by the H5-H6 loop, H6, and H7. Moreover, the residues lining the pathways were analyzed for their roles in ligand unbinding. Based on our results, the possible structural modification strategies on GW4064 were also proposed.

Resumo Limpo

farnesoid x receptor fxr nrh member nuclear receptor superfamili play import role bile acid homeostasi lipoprotein glucos metabol hepat regener gw potent select fxr agonist becom tool compound probe physiolog function fxr now mechan gw enter leav fxr pocket still poor understood report comput studi gw unbind pathway fxr use sever molecular dynam md simul techniqu base crystal structur fxr complex gw convent md first use refin bind check stabil gw fxr pocket random acceler md simul perform explor possibl unbind pathway gw fxr four main pathway cluster found among three subpathway name path b b observ frequent multipl steer md simul employ estim maximum ruptur forc sum forc character intermedi state ligand unbind process compar averag forc profil structur chang path b identifi favor unbind pathway former locat hh loop hh loop latter locat cleft form hh loop h h moreov residu line pathway analyz role ligand unbind base result possibl structur modif strategi gw also propos

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