Molecular dynamics of buspirone analogues interacting with the 5-HT1A and 5-HT2A serotonin receptors
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Introduction
The serotonin receptors (except for the 5-HT3 receptor) are members of the rhodopsin family of G-protein-coupled receptors (GPCRs).1 Recently, an X-ray crystal structure of rhodopsin at 2.8 Å resolution was reported.2 This is the first experimental structure of a GPCR at an atomic resolution, and the organisation of the seven transmembrane helices (TMHs) confirms the suggested α-carbon template for the TMHs in the rhodopsin family of GPCRs.3 GPCRs are integral membrane proteins consisting of seven transmembrane-spanning α-helices (TMHs), connected by three intracellular (Is) and three extracellular (Es) loops forming a central core. The available data indicate that binding of small ligands (neurotransmitters, drugs) to GPCRs involves amino-acids within the central core.3
Clinical trials have shown that buspirone, which is structurally unrelated to the benzodiazepines, has anxiolytic and anti-depressive properties.4, 5, 6 Buspirone is a relatively potent but non-selective partial agonist at 5-HT1A serotonin receptors,4 and its anxiolytic effects are assumed to be related to its 5-HT1A receptor affinity.4, 5, 6 In general, the buspirone analogues have some important advantages over other groups of anxiolytics, such as the benzodiazepines; they do not cause a sedative effect, the toxicity is relatively small, they are not addictive, and they have no associated withdrawal syndrome.7 The introduction of buspirone as a clinically efficacious anxiolytic drug has focused attention on the 5-HT1A receptor as a possible molecular site for anxiolytic drug action, and several buspirone analogues have been synthesised and tested for their 5-HT1A receptor affinities.8
There are indications that 5-HT2A, 5-HT2B and 5-HT2C receptors may also be targets for anxiolytic drugs.9, 10 Mixed 5-HT2A/2C receptor antagonists, like ritanserin, have anxiolytic properties in animal models11 and in clinical trials.12 Ligands combining agonist properties at presynaptic 5-HT1A receptors with antagonist properties at 5-HT2A/2C receptors may have greater efficacy than buspirone in producing anxiolytic effects.13 To rationalise the design of new compounds with a therapeutic potential in the treatment of anxiety, more information about the structural determinates for 5-HT1A and 5-HT2A/2C receptor specific binding, and about the conformational states of the receptor induced by different ligands is necessary.
Computational chemistry techniques have proved to be valuable tools for a better understanding of the molecular events involved in drug specificity and selectivity and for the study of protein dynamics. In the present study, three-dimensional (3-D) models of the human serotonin 5-HT1A and 5-HT2A receptors were constructed by computational chemistry techniques based on the suggested α-carbon template for the TMHs in the rhodopsin family of GPCRs.3 The models were used to study structural determinants for 5-HT1A and 5-HT2A receptor selectivity of buspirone and three of its analogues (Table 1), and to study the different conformational states of the receptors induced by the buspirone analogues.
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Conformational analysis of the ligands
In order to obtain low-energy conformers that might interact with the receptors, the conformational space of the ligand molecules (Table 1) were explored by molecular dynamics (MD) simulations. Conformers obtained during MD simulations were analysed, and the conformers with a structure in accordance with the biophore model of the 5-HT1A receptor or the 5-HT2A receptor (Fig. 1) were energy-minimised. The results of the conformational analysis of ligands ()–() (Table 1) are shown in Table 2.
Discussion
The present models of 5-HT1A and 5-HT2A serotonin receptors were constructed with the helical parts organised according to the suggested α-carbon atom template of GPCRs.3 This template was confirmed by the recent experimental X-ray structure of bovine rhodopsin at 2.8 Å resolution.2 At 2.8 Å resolution, it is not possible to identify internal hydrogen bonds and side-chain torsional angels from the X-ray density map, and the experimental model must be considered as relatively crude. Several
Conclusion
The present models of the 5-HT1A and 5-HT2A receptors indicated that an asparagine in TMH1 (Asn54 in 5-HT1A, Asn92 in 5-HT2A), aspartic acid in TMH2 (Asp82 in the 5-HT1A receptor, Asp120 in 5-HT2A), a serine in TMH3 (Ser123 in 5-HT1A and Ser162 in 5-HT2A), asparagine in TMH7 (Asn396 in 5-HT1A, Asn375 in 5-HT2A) and proline in TMH7(Pro397 in 5-HT1A and Pro376 in 5-HT2A) form interhelical contacts that constrain TMH1, 2, 3 and 7 relative to each others. Simulations of receptor–ligand interactions
Methods
Molecular mechanic energy minimisation (MM) and MD simulations were performed with the AMBER 5.0 all atom force field.39 Explicit solvent molecules were not included in the calculations, and a distance-dependent dielectric function (ε=4r, r: inter-atomic distance) was used to include the solvent effects. MM energy minimisation of ligand molecules and of averaged receptor–ligand complexes after MD simulations were performed using 0.002 kcal/mol Å for the norm of the energy gradient as convergence
Acknowledgements
This work was supported by grants from the Pharmaceutical Research Institute, Warsaw, Poland, and by computer time on the HP RISC supercomputer at the University of Tromsø, Norway.
References (46)
- et al.
Neuropharmacology
(1999) - et al.
J. Mol. Biol.
(1997) - et al.
Trends Pharmacol. Sci.
(1987) - et al.
J. Mol. Biol.
(1990) - et al.
J. Mol. Biol.
(1999) - et al.
J. Biol. Chem.
(1995) T.I.P.S.
(1998)- et al.
J. Biol. Chem.
(1996) Curr. Opin. Biotech
(1994)- et al.
FEBS Lett.
(1992)
Brain Res. Mol. Brain Res.
Biochem. Pharmacol.
Science
Drugs
CNS Drugs
CNS Drugs
J. Med. Chem.
J. Med. Chem.
Br. J. Pharmacol.
Drug Develop. Res.
Psychopharnacology
J. Pharmacol. Exp. Ther.
Arch. Pharm. Pharm. Med. Chem.
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