Evaluation of the binding performance of flavonoids to estrogen receptor alpha by Autodock, Autodock Vina and Surflex-Dock

Molecular docking is a widely used method to predict the binding modes of small-molecule ligands to the target binding site. However, it remains a challenge to identify the correct binding conformation and the corresponding binding affinity for a series of structurally similar ligands, especially those with weak binding. An understanding of the various relative attributes of popular docking programs is required to ensure a successful docking outcome. In this study, we systematically compared the performance of three popular docking programs, Autodock, Autodock Vina, and Surflex-Dock for a series of structurally similar weekly binding flavonoids (22) binding to the estrogen receptor alpha (ER alpha). For these flavonoids-ER alpha interactions, Surflex-Dock showed higher accuracy than Autodock and Autodock Vina. The hydrogen bond overweighting by Autodock and Autodock Vina led to incorrect binding results, while Surflex-Dock effectively balanced both hydrogen bond and hydrophobic interactions. Moreover, the selection of initial receptor structure is critical as it influences the docking conformations of flavonoids-ER alpha complexes. The flexible docking method failed to further improve the docking accuracy of the semi-flexible docking method for such chemicals. In addition, binding interaction analysis revealed that 8 residues, including Ala350, Glu353, Leu387, Arg394, Phe404, Gly521, His524, and Leu525, are the key residues in ER alpha-flavonoids complexes. This work provides reference for assessing molecular interactions between ER alpha and flavonoid-like chemicals and provides instructive information for other environmental chemicals.

Automated summary

Molecular docking is a widely used method to predict the binding modes of small-molecule ligands to the target binding site. In this study, the performance of three popular docking programs, Autodock, Autodock Vina, and Surflex-Dock, was systematically compared for a series of structurally similar flavonoids binding to the estrogen receptor alpha (ER alpha). The results showed that Surflex-Dock exhibited higher accuracy than Autodock and Autodock Vina. The hydrogen bond overweighting by Autodock and Autodock Vina led to incorrect binding results, while Surflex-Dock effectively balanced both hydrogen bond and hydrophobic interactions. The selection of initial receptor structure was also found to be critical for the docking conformation. Moreover, key residues in ER alpha-flavonoids complexes were identified.