Journal of Molecular Modeling

, Volume 19, Issue 4, pp 1751–1762 | Cite as

Determination of key receptor–ligand interactions of dopaminergic arylpiperazines and the dopamine D2 receptor homology model

  • Vladimir SukalovicEmail author
  • Vukic Soskic
  • Milan Sencanski
  • Deana Andric
  • Sladjana Kostic-Rajacic
Original Paper


Interest in structure-based G-protein-coupled receptor (GPCR) ligand discovery is huge, given that almost 30 % of all approved drugs belong to this category of active compounds. The GPCR family includes the dopamine receptor subtype D2 (D2DR), but unfortunately—as is true of most GPCRs—no experimental structures are available for these receptors. In this publication, we present the molecular model of D2DR based on the previously published crystal structure of the dopamine D3 receptor (D3DR). A molecular modeling study using homology modeling and docking simulation provided a rational explanation for the behavior of the arylpiperazine ligand. The observed binding modes and receptor–ligand interactions provided us with fresh clues about how to optimize selectivity for D2DR receptors.


Arylpiperazine ligand positioned inside dopamine D2 receptor bind site showing key amino acid residues

Open image in new window


Dopamine Molecular modeling Arylpiperazine Docking simulations 



Dopamine receptor type 2


Extracellular loop




Dopamine receptor type 3



This research formed part of project 172032 funded by the Ministry of Education and Science, Republic of Serbia.

PARADOX cluster at the Scientific Computing Laboratory of the Institute of Physics Belgrade, is supported in part by the Serbian Ministry of Education and Science under project no. ON171017, and by the European Commission under FP7 projects HP-SEE, PRACE-1IP, PRACE-2IP, EGI-InSPIRE.

Supplementary material

894_2012_1731_Fig5_ESM.jpg (513 kb)

(JPEG 513 kb)

894_2012_1731_Fig6_ESM.jpg (317 kb)

(JPEG 316 kb)

894_2012_1731_Fig7_ESM.jpg (1.6 mb)

(JPEG 1595 kb)

894_2012_1731_Fig8_ESM.jpg (423 kb)

(JPEG 423 kb)

894_2012_1731_Fig9_ESM.jpg (329 kb)

(JPEG 328 kb)

894_2012_1731_Fig10_ESM.jpg (247 kb)

(JPEG 247 kb)

894_2012_1731_Fig11_ESM.jpg (207 kb)

(JPEG 206 kb)

894_2012_1731_Fig12_ESM.jpg (107 kb)

(JPEG 106 kb)

894_2012_1731_Fig13_ESM.jpg (140 kb)

(JPEG 140 kb)

894_2012_1731_MOESM1_ESM.xls (26 kb)
ESM 10 (XLS 26 kb)


  1. 1.
    Carlsson J, Coleman RG, Setola V, Irwin JJ, Fan H, Schlessinger A, Sali A, Roth BL, Shoichet BK (2011) Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat Chem Biol 7(11):769–778CrossRefGoogle Scholar
  2. 2.
    Filizola M, Devi LA (2012) Structural biology: how opioid drugs bind to receptors. Nature 485(7398):314–317CrossRefGoogle Scholar
  3. 3.
    Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330:1091–1095CrossRefGoogle Scholar
  4. 4.
    Sukalovic V, Ignjatovic D, Tovilovic G, Andric D, Shakib K, Kostic-Rajacic S, Soskic V (2012) Interactions of N- {[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1- {[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas with dopamine D2 and 5-hydroxytryptamine 5HT(1A) receptors. Bioorg Med Chem Lett 22(12):3967–3972CrossRefGoogle Scholar
  5. 5.
    Newman AH, Beuming T, Banala AK, Donthamsetti P, Pongetti K, Labounty A, Levy B, Cao J, Michino M, Luedtke RR, Javitch JA, Shi L (2012) Molecular determinants of selectivity and efficacy at the dopamine D3 receptor. J Med Chem 55(15):6689–6699CrossRefGoogle Scholar
  6. 6.
    National Center for Biotechnology Information (2012) The National Center for Biotechnology Information advances science and health database. Accessed 27 Dec 2012
  7. 7.
    Van Munster BC, de Rooij SE, Yazdanpanah M, Tienari PJ, Pitkala KH, Osse RJ, Adamis D, Smit O, van der Steen MS, van Houten M, Rahkonen T, Sulkava R, Laurila JV, Strandberg TE, Tulen JH, Zwang L, MacDonald AJ, Treloar A, Sijbrands EJ, Zwinderman AH, Korevaar JC (2010) The association of the dopamine transporter gene and the dopamine receptor 2 gene with delirium, a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 153B(2):648–655Google Scholar
  8. 8.
    Accelrys Software Inc. (2009) Discovery Studio Modeling Environment, release 2.5. Accelrys Software Inc., San DiegoGoogle Scholar
  9. 9.
    Teeter MM, Froimowitz M, Stec B, DuRand CJ (1994) Homology modeling of the dopamine D2 receptor and its testing by docking of agonists and tricyclic antagonists. J Med Chem 37(18):2874–2888CrossRefGoogle Scholar
  10. 10.
    Humphrey W, Dalke A, Schulten K (1996) VMD—visual molecular dynamics. J Molec Graph 14:33Google Scholar
  11. 11.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Montgomery JA Jr, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004) Gaussian 03, revision E.01. Gaussian, Inc., WallingfordGoogle Scholar
  12. 12.
    Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, Darian E, Guvench O, Lopes P, Vorobyov I, MacKerell AD Jr (2010) CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force field. J Comput Chem 31:671–690Google Scholar
  13. 13.
    Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802CrossRefGoogle Scholar
  14. 14.
    PARADOX cluster at the Scientific Computing Laboratory of the Institute of Physics Belgrade Accessed 27 Dec 2012
  15. 15.
    European Bioinformatics Institute Accessed 27 Dec 2012
  16. 16.
    Javitch JA (1998) Mapping the binding-site crevice of the D2 receptor. Adv Pharmacol 42:412–415CrossRefGoogle Scholar
  17. 17.
    Javitch JA, Fu D, Chen J, Karlin A (1995) Mapping the binding-site crevice of the dopamine D2 receptor by the substituted-cysteine accessibility method. Neuron 14(4):825–831CrossRefGoogle Scholar
  18. 18.
    Schrödinger, LLC (2011) Glide, version 5.7. Schrödinger, LLC, New YorkGoogle Scholar
  19. 19.
    Javitch JA, Ballesteros JA, Weinstein H, Chen J (1998) A cluster of aromatic residues in the sixth membrane-spanning segment of the dopamine D2 receptor is accessible in the binding-site crevice. Biochemistry 37(4):998–1006CrossRefGoogle Scholar
  20. 20.
    Accelrys Software Inc. (2009) Discovery Studio Modeling environment, release 2.5: Discovery Studio Visualiser 2.5.1. Accelrys Software Inc., San DiegoGoogle Scholar
  21. 21.
    Persistence of Vision Raytracer Ltd. (2003–2007) Persistence of Vision Raytracer (POV-Ray).
  22. 22.
    Shi L, Javitch JA (2004) The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice. Proc Natl Acad Sci USA 101(2):440–445Google Scholar
  23. 23.
    Sukalovic V, Zlatovic M, Andric D, Roglic G, Kostic-Rajaccic S, Soskic V (2004) Modeling of the D2 dopamine receptor arylpiperazine binding site for 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4-arylpiperazines. Arch Pharm (Weinheim) 337(9):502–512CrossRefGoogle Scholar
  24. 24.
    Sukalovic V, Zlatovic M, Andric D, Roglic G, Kostic-Rajacic S, Soskic V (2005) Interaction of arylpiperazines with the dopamine receptor D2 binding site. Arzneimittelforschung 55(3):145–152Google Scholar
  25. 25.
    Gloriam E, Foord M, Blaney E, Garland L (2009) Definition of the G protein-coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design. J Med Chem 52(14):4429–4442Google Scholar
  26. 26.
    Bondensgaard K, Ankersen M, Thøgersen H, Hansen B, Wulff B, Bywater R (2004) Recognition of privileged structures by G-protein coupled receptors. J Med Chem 47(4):888–899CrossRefGoogle Scholar
  27. 27.
    Dukic S, Vujovic M, Soskic V, Joksimovic J (1997) Structure–affinity relationship studies on D-2/5-HT1A receptor ligands. 4-(2-Heteroarylethyl)-1-arylpiperazines. Arzneimittelforschung 47(3):239–243Google Scholar
  28. 28.
    Kostic-Rajacic S, Soskic V, Joksimovic J (1998) Mixed dopaminergic/serotonergic properties of several 2-substituted 4-[2-(5-benzimidazole)ethyl]-1-arylpiperazines. Arch Pharm (Weinheim) 331(1):22–26CrossRefGoogle Scholar
  29. 29.
    Newman AH, Grundt P, Cyriac G, Deschamps JR, Taylor M, Kumar R, Ho D, Luedtke RR (2009) N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists. J Med Chem 52(8):2559–2570CrossRefGoogle Scholar
  30. 30.
    Schlotter K, Boeckler F, Hubner H, Gmeiner P (2005) Fancy bioisosteres: metallocene-derived G-protein-coupled receptor ligands with subnanomolar binding affinity and novel selectivity profiles. J Med Chem 48(11):3696–3699CrossRefGoogle Scholar
  31. 31.
    Soskic V, Dukic S, Dragovic D, Joksimovic J (1996) Synthesis of N-n-propyl-N-(2-arylethyl)-5-(1H-benzimidazol-2-thione)-ethylamines and related compounds as potential dopaminergic ligands. Arzneimittelforschung 46(8):741–746Google Scholar
  32. 32.
    Hackling A, Ghosh R, Perachon S, Mann A, Holtje HD, Wermuth CG, Schwartz JC, Sippl W, Sokoloff P, Stark H (2003) N-(omega-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands. J Med Chem 46(18):3883–3899CrossRefGoogle Scholar
  33. 33.
    Ehrlich K, Gotz A, Bollinger S, Tschammer N, Bettinetti L, Harterich S, Hubner H, Lanig H, Gmeiner P (2009) Dopamine D2, D3, and D4 selective phenylpiperazines as molecular probes to explore the origins of subtype specific receptor binding. J Med Chem 52(15):4923–4935CrossRefGoogle Scholar
  34. 34.
    Grundt P, Carlson EE, Cao J, Bennett CJ, McElveen E, Taylor M, Luedtke RR, Newman AH (2005) Novel heterocyclic trans olefin analogues of N- {4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor. J Med Chem 48(3):839–848CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Vladimir Sukalovic
    • 1
    Email author
  • Vukic Soskic
    • 2
  • Milan Sencanski
    • 3
  • Deana Andric
    • 4
  • Sladjana Kostic-Rajacic
    • 1
  1. 1.ICTM—Centre for ChemistryUniversity of BelgradeBelgradeSerbia
  2. 2.ORGENTEC Diagnostika GmbHMainzGermany
  3. 3.Innovation Center of the Faculty of ChemistryUniversity of BelgradeBeogradSerbia
  4. 4.Faculty of ChemistryUniversity of BelgradeBeogradSerbia

Personalised recommendations