Skip to main content

Advertisement

SpringerLink
Log in

Structural features of GABAA receptor antagonists: pharmacophore modeling and 3D-QSAR studies

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Pharmacophore modeling, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) studies have been carried out on 5-(4-piperidyl)-3-isoxazolol (4-PIOL) analogs as GABAA receptor antagonists in this study. The best pharmacophore hypothesis generated by PHASE was ADHPR.6, which comprised a hydrogen bond acceptor (A), a hydrogen bond donor (D), a hydrophobic group (H), a positively charged group (P), and an aromatic ring (R). The pharmacophore model provided a good alignment for the further 3D-QSAR analyses, which presented a good R 2 value of 0.943, 0.930, and 0.916 for atom-based QSAR model, CoMFA model, and CoMSIA model, respectively. All QSAR models presented good statistical significance and predictivity, the corresponding Q 2 values for each 3D-QSAR model are 0.794, 0.569, and 0.637, respectively. Both pharmacophore and CoMSIA results showed that the hydrophobic sites are the key structural feature for GABAA receptor antagonists with high activities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Ai Y, Wang ST, Tang C, Sun PH, Song FJ (2011) 3D-QSAR and docking studies on pyridopyrazinones as BRAF inhibitors. Med Chem Res 20(8):1298–1317

    Article  CAS  Google Scholar 

  • Almerico AM, Tutone M, Lauria A (2010) 3D-QSAR pharmacophore modeling and in silico screening of new Bcl-xl inhibitors. Eur J Med Chem 45(11):4774–4782. doi:10.1016/j.ejmech.2010.07.042

    Article  CAS  PubMed  Google Scholar 

  • Chebib M, Johnston GAR (1999) The ‘ABC’ of GABA receptors: a brief review. Clin Exp Pharmacol Physiol 26(11):937–940. doi:10.1046/j.1440-1681.1999.03151.x

    Article  CAS  PubMed  Google Scholar 

  • Cramer RD (2010) Rethinking 3D-QSAR. J Comput Aided Mol Des 25(3):197–201. doi:10.1007/s10822-010-9403-z

    Article  PubMed Central  PubMed  Google Scholar 

  • D’Hulst C, Atack JR, Kooy RF (2009) The complexity of the GABAA receptor shapes unique pharmacological profiles. Drug Discov Today 14(17–18):866–875. doi:10.1016/j.drudis.2009.06.009

    Article  PubMed  Google Scholar 

  • Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA (2006) PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J Comput Aided Mol Des 20(10–11):647–671. doi:10.1007/s10822-006-9087-6

    Article  CAS  PubMed  Google Scholar 

  • Frolund B, Kristiansen U, Brehm L, Hansen AB, Krogsgaardlarsen P, Falch E (1995) PARTIAL GABA(A) RECEPTOR AGONISTS - SYNTHESIS AND IN-VITRO PHARMACOLOGY OF A SERIES OF NONANNULATED ANALOGS OF 4,5,6,7-TETRAHYDROISOXAZOLO 5,4-C PYRIDIN-3-OL. J Med Chem 38(17):3287–3296. doi:10.1021/jm00017a014

    Article  CAS  PubMed  Google Scholar 

  • Frolund B, Tagmose L, Liljefors T, Stensbol TB, Engblom C, Kristiansen U, Krogsgaard-Larsen P (2000) A novel class of potent 3-isoxazolol GABA(A) antagonists: design, synthesis, and pharmacology. J Med Chem 43(26):4930–4933. doi:10.1021/jm000371q

    Article  CAS  PubMed  Google Scholar 

  • Frolund B, Jorgensen AT, Tagmose L, Stensbol TB, Vestergaard HT, Engblom C, Kristiansen U, Sanchez C, Krogsgaard-Larsen P, Liljefors T (2002) Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling. J Med Chem 45(12):2454–2468. doi:10.1021/jm020027o

    Article  CAS  PubMed  Google Scholar 

  • Frolund B, Tagmose L, Jorgensen AT, Kristiansen U, Stensbol TB, Lijefors T, Krogsgaard-Larsen P (2003) Design and synthesis of a new series of 4-alkylated 3-isoxazolol GABA(A) antagonists. Eur J Med Chem 38(4):447–449. doi:10.1016/s0223-5234(03)00056-4

    Article  CAS  PubMed  Google Scholar 

  • Frolund B, Jensen LS, Guandalini L, Canillo C, Vestergaard HT, Kristiansen U, Nielsen B, Stensbol TB, Madsen C, Krogsgaard-Larszen P, Liljefors T (2005) Potent 4-aryl- or 4-arylalkyl-substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling. J Med Chem 48(2):427–439. doi:10.1021/jm049256w

    Article  CAS  PubMed  Google Scholar 

  • Frolund B, Jensen LS, Storustovu SI, Stensbol TB, Ebert B, Kehler J, Krogsgaard-Larsen P, Liljefors T (2007) 4-aryl-5-(4-piperidyl)-3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and structure-activity relationships. J Med Chem 50(8):1988–1992. doi:10.1021/jm070038n

    Article  CAS  PubMed  Google Scholar 

  • Ghoshal N, Vijayan RSK (2010) Pharmacophore models for GABAA modulators: implications in CNS drug discovery. Expert Opin Drug Discov 5(5):441–460

    Article  CAS  PubMed  Google Scholar 

  • Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph Model 20(4):269–276

    Article  CAS  PubMed  Google Scholar 

  • Gramatica P (2007) Principles of QSAR models validation: internal and external. QSAR Comb Sci 26(5):694–701

    Article  CAS  Google Scholar 

  • Guasch L, Sala E, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S (2012) Development of docking-based 3D-QSAR models for PPARgamma full agonists. J Mol Graph Model 36:1–9

    Article  CAS  PubMed  Google Scholar 

  • Korpi ER, Sinkkonen ST (2006) GABAA receptor subtypes as targets for neuropsychiatric drug development. Pharmacol Ther 109(1–2):12–32. doi:10.1016/j.pharmthera.2005.05.009

    Article  CAS  PubMed  Google Scholar 

  • Korpi ER, Grunder G, Luddens H (2002) Drug interactions at GABAA receptors. Prog Neurobiol 67(2):113–159

    Article  CAS  PubMed  Google Scholar 

  • Krehan D, Storustovu SI, Lijefors T, Ebert B, Nielsen B, Krogsgaard-Larsen P, Frolund B (2006) Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology. J Med Chem 49(4):1388–1396. doi:10.1021/jm050987l

    Article  CAS  PubMed  Google Scholar 

  • Lan P, Chen WN, Huang ZJ, Sun PH, Chen WM (2011) Understanding the structure-activity relationship of betulinic acid derivatives as anti-HIV-1 agents by using 3D-QSAR and docking. J Mol Model 17(7):1643–1659

    Article  CAS  PubMed  Google Scholar 

  • Li YS, Zhou L, Ma X (2012) Molecular docking and 3D QSAR studies of substituted 4-amino-1H-pyrazolo 3,4-d pyrimidines as insulin-like growth factor-1 receptor (IGF1R) inhibitors. Med Chem Res 21(10):3301–3311. doi:10.1007/s00044-011-9877-9

    Article  CAS  Google Scholar 

  • Lu P, Wei X, Zhang R (2010) CoMFA and CoMSIA 3D-QSAR studies on quionolone caroxylic acid derivatives inhibitors of HIV-1 integrase. Eur J Med Chem 45(8):3413–3419

    Article  CAS  PubMed  Google Scholar 

  • Mehta N, Chand S, Bahia MS, Silakari O (2012) Elaboration of new anti-inflammatory agents using pharmacophore based 3D QSAR of 4, 5-diaryl imidazoline as P2X(7) receptor antagonists. Lett Drug Des Discov 9(2):185–198

    Article  CAS  Google Scholar 

  • Møller HA, Sander T, Kristensen JL, Nielsen B, Krall J, Bergmann ML, Christiansen B, Balle T, Jensen AA, Frølund B (2010) Novel 4-(Piperidin-4-yl)-1-hydroxypyrazoles as γ-aminobutyric AcidAReceptor ligands: synthesis, pharmacology, and structure–activity relationships. J Med Chem 53(8):3417–3421. doi:10.1021/jm100106r

    Article  PubMed  Google Scholar 

  • Nagamani S, Muthusamy K, Kirubakaran P, Singh KD, Krishnasamy G (2012) Theoretical studies on benzimidazole derivatives as E. coli biotin carboxylase inhibitors. Med Chem Res 21(9):2169–2180. doi:10.1007/s00044-011-9738-6

    Article  CAS  Google Scholar 

  • Nair SB, Teli MK, Pradeep H, Rajanikant G (2012) Computational identification of novel histone deacetylase inhibitors by docking based QSAR. Comput Biol Med 42(6):697–705

    Article  CAS  PubMed  Google Scholar 

  • Neaz M, Pasha F, Muddassar M, Lee SH, Sim T, Hah JM, Cho SJ (2009) Pharmacophore based 3D-QSAR study of VEGFR-2 inhibitors. Med Chem Res 18(2):127–142

    Article  CAS  Google Scholar 

  • Olsen RW, Sieghart W (2009) GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56(1):141–148. doi:10.1016/j.neuropharm.2008.07.045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • PHASE 3.1 (2009) Usermanual. Schrödinger. LLC, New York

    Google Scholar 

  • Reddy KK, Singh SK, Dessalew N, Tripathi SK, Selvaraj C (2012) Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors. J Enzyme Inhib Med Chem 27(3):339–347. doi:10.3109/14756366.2011.590803

    Article  CAS  PubMed  Google Scholar 

  • Sander T, Frolund B, Bruun AT, Ivanov I, McCammon JA, Balle T (2011) New insights into the GABA(A) receptor structure and orthosteric ligand binding: receptor modeling guided by experimental data. Proteins-Struct Funct Bioinf 79(5):1458–1477. doi:10.1002/prot.22975

    Article  CAS  Google Scholar 

  • Schwab CH (2010) Conformations and 3D pharmacophore searching. Drug Discov Today Technol 7(4):e245–e253. doi:10.1016/j.ddtec.2010.10.003

    Article  CAS  Google Scholar 

  • Sun X, Li Y, Li W, Xu Z, Tang Y (2011) Computational investigation of interactions between human H2 receptor and its agonists. J Mol Graph Model 29(5):693–701. doi:10.1016/j.jmgm.2010.12.001

    Article  CAS  PubMed  Google Scholar 

  • Telvekar VN, Chaudhari HK (2012) 3D-QSAR and docking-based combined in silico study on C-5 methyl substituted 4-arylthio and 4-aryloxy-3-iodopyridin-2-(1H)-one as HIV-1 RT inhibitors. Med Chem Res 21(8):2032–2043. doi:10.1007/s00044-011-9720-3

    Article  CAS  Google Scholar 

  • Vestergaard HT, Cannillo C, Frølund B, Kristiansen U (2007) Differences in kinetics of structurally related competitive GABAA receptor antagonists. Neuropharmacology 52(3):873–882. doi:10.1016/j.neuropharm.2006.10.004

    Article  CAS  PubMed  Google Scholar 

  • Weber KC, Salum LB, Honório KM, Andricopulo AD, da Silva ABF (2010) Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT1A receptor ligands. Eur J Med Chem 45(4):1508–1514. doi:10.1016/j.ejmech.2009.12.059

    Article  CAS  PubMed  Google Scholar 

  • Zhu H, Fang H, Cheng X, Wang Q, Zhang L, Feng J, Xu W (2009) 3D-QSAR study of pyrrolidine derivatives as matrix metalloproteinase-2 inhibitors. Med Chem Res 18(8):683–701

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank for the financial supports from National Natural Science Foundation of China (21172070), National Key Technology R&D Program of China (2011BAE06B05), National High Technology Research Development Program of China (2011AA10A207), National Basic Research Program of China (2010CB126100), and the Fundamental Research Funds for the Central Universities.

Author information

Authors and Affiliations

  1. Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, PO Box 544, 130 Meilong Road, Shanghai, 200237, People’s Republic of China

    Wei Zhang, Shuang Xia, Jinjin Ye, Zhong Li, Weiping Zhu & Jiagao Cheng

  2. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, People’s Republic of China

    Yun Tang & Jiagao Cheng

Authors
  1. Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuang Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinjin Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yun Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Weiping Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiagao Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhong Li or Jiagao Cheng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, W., Xia, S., Ye, J. et al. Structural features of GABAA receptor antagonists: pharmacophore modeling and 3D-QSAR studies. Med Chem Res 22, 5961–5972 (2013). https://doi.org/10.1007/s00044-013-0583-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-013-0583-7

Keywords

Search

Navigation