Molecular modelling of UH-301 and 5-HTla receptor interactions |
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Authors: | Sylte, Ingebrigt Edvardsen, Oyvind Dahl, Svein G. |
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Affiliation: | Department of Pharmacology, Institute of Medical Biology, University of Tromso N-9037 Tromsø, Norway |
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Abstract: | A three-dimensional model of the human 5-HT1a receptor was constructedby molecular modelling, and the molecular and electronic structuresof (R)- and (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin(UH-301) and of (R)- and (S)-8-hydroxy-2-(dipropylamino)tetralin(8-OH-DPAT) were examined by molecular mechanics and quantummechanics calculations and molecular dynamics simulations. Thereceptor model has seven transmembrane helices (TMHs), organizedaccording to a projection map of visual rhodopsin, and includesall loops between helices and the N- and C-terminal parts. Interactionsof UH-301 and 8-OH-DPAT with the 5-HT1a receptor were examinedby molecular dynamics simulations and energy minimization ofreceptorligand complexes. 8-OH-DPAT had lower electrostaticpotentials around the hydroxyl group and stronger hydrogen bondingto the receptor model than had UH-301. The simulations indicatedthat the 5-HT1a receptor agonists, (R)- and (S)-8-OH-DPAT and(R)-UH-301, interacted with the receptor at a site closer toAsp82 in TMH2 than did (S)-UH-301, which is a 5-HT,1a receptorantagonist. Simulations of receptorligand complexes indicatedthat Asp82, Asp116, Ser199, Thr200 and De385 are essential forbinding of both agonist and antagonist to the receptor. |
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Keywords: | electrostatic potentials/ 5-HT1a receptor/ molecular dynamics/ 8-OH-DPAT/ receptor modelling/ UH-301 |
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