Abstract
A 3D-QSAR study on amino-substituted pyrido[3,2b]pyrazinones as PDE-5 inhibitors was successfully performed by means of pharmacophore mapping using PHASE module of Schrödinger-9. The 3D-QSAR obtained from AADHRR-183 hypothesis was found to be statistically good with r 2 = 0.95 and q 2 = 0.81 taking PLS factor 4. The statistical significance of the model was also confirmed by a high value of Fisher ratio of 85.1 and a very low value of RMSE 0.29. One of the other parameters which signify the model predictivity is Pearson R. Its value of 0.91 shows that the correlation between predicted and observed activities for the test set compounds is excellent. Hydrophobic groups are important for PDE-5 inhibition while H-bond donor groups are less favorable for the same. Electron withdrawing groups are favorable if include at ring A in the structures while unfavorable at other sites. Thus, it can be assumed that the present QSAR analysis is enough to demonstrate PDE-5 inhibition with the help of AADHRR-183 hypothesis and will help in designing novel and potent PDE-5 inhibitors.
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Abbreviations
- 3D-QSAR:
-
Three-dimensional quantitative structure–activity relationship
- 2D-QSAR:
-
Two-dimensional quantitative structure–activity relationship
- PDEs:
-
Phosphodiesterases
- RMSE:
-
Root mean squared error
- cAMP:
-
Cyclic monophosphate
- cGMP:
-
Cyclic guanosine monophosphate
- PLS:
-
Partial least square
- LOO:
-
Leave one out
- r 2 :
-
Cross-validated correlation coefficient
- q 2 :
-
Internal predictivity
References
Almerico AM, Tutone M, Lauria A (2010) 3D-QSAR pharmacophore modeling and in silico screening of new Bcl-xl inhibitors. Eur J Med Chem 45:4774–4782
Black KL, Yin D, Ong JM, Hu J, Konda BM, Wang X, Ko MK, Bayan JA, Sacapano MR, Espinoza A, Irvin DK, Shu Y (2008) PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. Brain Res 1230:290–302
Burnett AL (2005) Phosphodiesterase 5 mechanisms and therapeutic applications. Am J Cardiol 96:29–31
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 20:647–671
Eardley I, Donatucci C, Corbin J, El-Meliegy A, Hatzimouratidis K, McVary K, Munarriz R, Lee SW (2010) Pharmacotherapy for erectile dysfunction. J Sex Med 7:524–540
Francis SH, Corbin JD (1999) Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci 36:275–328
Haning H, Niewöhner U, Schenke T, Es-Sayed M, Schmidt G, Lampe T, Bischoff E (2002) Imidazo[5, 1-f][1, 2, 4]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors. Bioorg Med Chem Lett 12:865–868
Hosogai NH, Hamada K, Tomita M, Nagashima A, Takahashi T, Sekizawa T, Mizutani T, Urano Y, Kuroda A, Sawada K, Ozaki T, Seki J, Goto T (2001) FR226807: a potent and selective phosphodiesterase type 5 inhibitor. Eur J Pharmacol 428:295–302
Lather V, Kristam R, Saini JS, Karthikeyan NA, Balaji VN (2008) QSAR models for prediction of glycogen synthase kinase-3β inhibitory activity of indirubin derivatives. QSAR Comb Sci 27:718–728
LigPrep, version 2.3, Schrödinger, LLC, New York, NY, 2009
MacroModel, version 9.7, Schrödinger, LLC, New York, NY, 2009
Mahipal, Tanwar OP, Karthikeyan C, Moorthy NSHN, Trivedi P (2010) 3D-QSAR of aminophenyl benzamide derivatives as histone deacetylase inhibitors. Med Chem Res 6:277–285
Moreland RB, Goldstein I, Kim NN, Traish A (1999) Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: research and clinical implications in erectile dysfunction. TEM 10:97–104
Narkhede SS, Degani MS (2007) Pharmacophore refinement and 3D-QSAR studies of histamine H3 antagonists. QSAR Comb Sci 26:744–753
Owen DR, Walker JK, Jon Jacobsen E, Freskos JN, Hughes RO, Brown DL, Bell AS, Brown DG, Phillips C, Mischke BV, Molyneaux JM, Fobian YM, Heasley SE, Moon JB, Stallings WC, Joseph Rogier D et al (2009) Identification, synthesis and SAR of amino substituted pyrido[3, 2b]pyrazinones as potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 19:4088–4091
PHASE-3.1, Schrödinger, LLC, New York, NY, 2009
Samantha L, Cesare M, Aleksey K, Mattia S, Stefano M, Elena C, Dorotea R, Alessandro C (2008) SAR and QSAR study on 2-aminothiazole derivatives, modulators of transcriptional repression in Huntington’s disease. Bioorg Med Chem 16:5695–5703
Shah UA, Deokar HS, Kadam SS, Kulkarni VM (2010) Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors. Mol Divers 14:559–568
Terrett NK, Bell AS, Brown D, Ellis P (1996) Sildenafil (viagra), a potent and selective inhibitor of type 5 cgmp phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett 6:1819–1824
Wall ME, Francis SH, Corbin JD, Grimes K, Jannetta RR, Kotera J, Macdonald BA, Gibson RR, Trewhella J (2003) Mechanisms associated with cGMP binding and activation of cGMP-dependent protein kinase. PNAS 100:2380–2385
Wallace WD (2005) Available and future treatments for erectile dysfunction. Clinical Cornerstone 1:37–44
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The authors are thankful to University Grants Commission, New Delhi, India for providing financial support. The authors also wish to acknowledge the team of Schrödinger for providing software facility.
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Tanwar, O., Saha, R., Alam, M.M. et al. 3D-QSAR of amino-substituted pyrido[3,2B]pyrazinones as PDE-5 inhibitors. Med Chem Res 21, 202–211 (2012). https://doi.org/10.1007/s00044-010-9523-y
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DOI: https://doi.org/10.1007/s00044-010-9523-y