(627c) Novel Computational Protocol for Small-Molecule : Protein Receptor Docking; Application to 1,4-Dhna and Tcdd Binding to AhR Mouse Protein
In this study, we applied our docking protocol to determine the binding of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA) and TCDD to the mouse AhR protein . The most energetically favored binding mode of TCDD with the AhR based on our docking protocol is in high accordance with previous experimental and computational studies examining this interaction [2, 3, 4, 5, 6]. The most energetically favored binding mode of 1,4-DHNA shows that both 1,4-DHNA and TCDD predominantly form strong interactions with the same residues of AhR. More polar interactions occur in the AhR : 1,4-DHNA complex in comparison to the AhR : TCDD complex due, in part, to differences in overall charge and substituent interactions with various amino acid side-chains. Association free energy calculations suggest that 1,4-DHNA binds with a lower affinity. This result is consistent with experimental observations showing similar efficacies of 1,4-DHNA and TCDD as AhR agonists but differences in their potencies . The strong agreement of our work in comparison with previous studies investigating TCDD in complex with AhR support the validity of our docking protocol and suggest that the computationally derived binding modes most likely represent the naturally occurring binding modes of TCDD and 1,4-DHNA with residues in the AhR ligand binding pocket.
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