Binding modes of series of new compounds containing a benzoxazole moiety bridged to an arylpiperazine by different thioether chains to 5-HT_1A receptor were investigated by means of molecular docking. The correlation of the binding affinity with the length of thioether spacer was observed experimentally: three-unit spacer caused at least 100-fold decrease in K_i compared to longer spacers. Automated docking with pharmacophoric constraints revealed the structural cause of this correlation. Possible interactions between Tyr7.43 and thioether fragment of the spacer caused the weakening of interactions from arylpiperazine part of the ligand. Additionally, the benzoxazole moiety of three-unit spacer compounds could hardly form any interactions with the transmembrane part of the receptor. On the contrary, for the compounds with longer spacers, not only the arylpiperazine moiety occupied optimal position in the binding pocket, but also benzoxazole was shown to form favorable interactions (H-bonds, π-π stacking) with residues in the third and seventh transmembrane helices. It is also shown, that the extended conformations for those flexible, long-chain molecules are both observed by MNR measurements and predicted by modeling techniques.

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