Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor
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Human dopamine D4 receptor is a GPCR target in the treatment of neurological and psychiatric conditions such as schizophrenia and Parkinson’s disease. The X-ray structure of this receptor has not been resolved so far. Therefore, a proper 3D structure of D4 could provide a good tool in order to design novel ligands against this target. In this study, homology modeling studies were performed to obtain a reasonable structure of the receptor using known templates. The obtained model was subjected to molecular dynamic simulation within a DPPC membrane system. Some structural features of the receptor such as a conserved disulfide bridge and ionic lock were considered in the modeling experiments. The resulted trajectories of simulation were clustered based on the root mean square deviation of the backbone. Some known ligands and decoys were accordingly docked into the representative frames of each cluster. The best final model was finally selected based on its ability to discriminate between active ligands and inactive decoys (ROC = 0.839). The presented model of human D4 receptor could be a promising starting point in future studies of drug design for the described target.
KeywordsBinding site Docking Homology modeling Human dopamine D4 receptor Molecular dynamic simulation
The support from the Research Council at Shiraz University of Medical Sciences is acknowledged. The authors would like to thank Nazanin Bagherzadeh for her kind contribution in language editing of the manuscript. This work is a PharmD dissertation report, performed by Minasadat Khoddami, student of pharmacy at Shahid Sadoughi University of Medical Sciences.
- 8.Enguehard-Gueiffier C, Hübner H, El Hakmaoui A, Allouchi H, Gmeiner P, Argiolas A, Melis MR, Gueiffier A (2006) 2-[(4-phenylpiperazin-1-yl) methyl] imidazo (di) azines as selective D4-ligands. Induction of penile erection by 2-[4-(2-methoxyphenyl) piperazin-1-ylmethyl] imidazo [1, 2-a] pyridine (PIP3EA), a potent and selective D4 partial agonist. J Med Chem 49(13):3938–3947CrossRefGoogle Scholar
- 12.Arora J, Bordeleau M, Dube L, Jarvie K, Mazzocco L, Peragine J, Tehim A, Egle I (2005) N-[(3S)-1-Benzylpyrrolidin-3-yl]-(2-thienyl)benzamides: human dopamine D4 ligands with high affinity for the 5-HT2A receptor. Bioorg Med Chem Lett 15(23):5253–5256. doi: 10.1016/j.bmcl.2005.08.051 CrossRefGoogle Scholar
- 17.De Brevern AG (2010) 3D structural models of transmembrane proteins. In: Membrane protein structure determination. Springer, Berlin pp 387–401Google Scholar
- 20.Becker O, Shacham S, Marantz Y, Noiman S (2003) Modeling the 3D structure of GPCRs: advances and application to drug discovery. Current opinion in drug discovery & development 6(3):353–361Google Scholar
- 29.Sonnhammer EL, von Heijne G, Krogh A (1998) A hidden Markov model for predicting transmembrane helices in protein sequences. Proc Int Conf Intell Syst Mol Biol 6:175-182Google Scholar
- 32.Hofman K (1993) TMbase-A database of membrane spanning protein segments. Biol Chem Hoppe-Seyler 374:166Google Scholar
- 36.Bernsel A, Viklund H, Hennerdal A, Elofsson A (2009) TOPCONS: consensus prediction of membrane protein topology. Nucleic Acids Res: gkp363Google Scholar
- 51.Triballeau N, Acher F, Brabet I, Pin J-P, Bertrand H-O (2005) Virtual screening workflow development guided by the “receiver operating characteristic” curve approach. Application to high-throughput docking on metabotropic glutamate receptor subtype 4. J Med Chem 48(7):2534–2547CrossRefGoogle Scholar