Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators

Journal of Molecular Modeling

Volumn 18, Issue 9, 2012, Pages 4437-4446

  Mueller, Ralf ^a   Dawson, Eric S ^a,b   Niswender, Colleen M ^a,b   Butkiewicz, Mariusz ^a   Hopkins, Corey R ^a,b   Weaver, C David ^a,b   Lindsley, Craig W ^a,b   Conn, P Jeffrey ^a,b   Meiler, Jens ^a,b  

^a VANDERBILT UNIVERSITY   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Enrichment; Machine learning; Metabotropic glutamate receptor subtype 4; Quantitative structure activity relationship; Virtual high throughput screening

Indexed keywords

METABOTROPIC RECEPTOR 4;

ALLOSTERISM; ARTICLE; ARTIFICIAL NEURAL NETWORK; HIGH THROUGHPUT SCREENING; HUMAN; PRIORITY JOURNAL; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

ALLOSTERIC REGULATION; ANIMALS; BENZOXAZOLES; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MODELS, MOLECULAR; NEURAL NETWORKS (COMPUTER); QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP; RATS; RECEPTORS, METABOTROPIC GLUTAMATE; ROC CURVE; SMALL MOLECULE LIBRARIES; USER-COMPUTER INTERFACE;

RODENTIA;

EID: 84867572613     PISSN: 16102940     EISSN: 09485023     Source Type: Journal    
DOI: 10.1007/s00894-012-1441-0     Document Type: Article

References (37)

1. Marino MJ, Conn PJ (2006) Glutamate-based therapeutic approaches: Allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol 6(1):98-102. doi:10.1016/ j.coph.2005.09.006
2. Marino MJ, Williams DL, O'Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, Conn PJ (2003) Allosteric modulation of group III metabotropic glutamate receptor 4: A potential approach to Parkinson's disease treatment. Proc Natl Acad Sci USA 100(23):13668-13673. doi:10.1073/pnas.1835724100
3. Marino M, Valenti O, Conn PJ (2003) Glutamate receptors and Parkinson's disease: Opportunities for intervention. Drugs Aging 20(5):377-397
4. MajM, Bruno V, Dragic Z, Yamamoto R, Battaglia G, InderbitzinW, Stoehr N, Stein T, Gasparini F, Vranesic I, Kuhn R, Nicoletti F, Flor PJ (2003) (-)-PHCCC, a positive allosteric modulator of mGluR4: Characterization, mechanism of action, and neuroprotection. Neuropharmacol 45(7):895-906. doi:10.1016/s0028-3908(03)00271-5
5. Mathiesen JM, Svendsen N, Bräuner-Osborne H, Thomsen C, Ramirez MT (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 andMPEP. Br J Pharmacol 138(6):1026-1030. doi:10.1038/sj.bjp.0705159
6. Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Veliçelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacol 38 (10):1493-1503. doi:10.1016/s0028-3908(99)00082-9
7. Gregory KJ, Dong EN, Meiler J, Conn PJ (2010) Allosteric Modulation of Metabotropic Glutamate Receptors: Structural Insights and Therapeutic Potential. Neuropharmacology. doi:10.1016/ j.neuropharm.2010.07.007
8. Lindberg JS, Culleton B, Wong G, Borah MF, Clark RV, Shapiro WB, Roger SD, Husserl FE, Klassen PS, Guo MD, Albizem MB, Coburn JW (2005) Cinacalcet HCl, an oral calcimimetic agent for the treatment of secondary hyperparathyroidism in hemodialysis and peritoneal dialysis: A randomized, double-blind, multicenter study. J Am Soc Nephrol 16(3):800-807. doi:10.1681/asn.2004060512
9. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M (2005) Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity. Antimicrob Agents Chemother 49(11):4721-4732. doi:10.1128/aac.49.11.4721-4732.2005
10. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3(8):711-716
11. Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, Thompson AD, Days EL, Nalywajko T, Austin CA,Williams MB, Ayala JE,Williams R, Lindsley CW, Conn PJ (2008) Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol 74(5):1345-1358. doi:10.1124/mol.108.049551
12. Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR (2009) Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) Positive Allosteric Modulators (PAMs). J Med Chem 52 (14):4115-4118. doi:10.1021/jm9005065
13. Niswender CM, Lebois EP, Luo Q, Kim K, Muchalski H, Yin H, Conn PJ, Lindsley CW (2008) Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators. Bioorg Med Chem Lett 18(20):5626-5630
14. Williams R, Niswender CM, Luo Q, Le U, Conn PJ, Lindsley CW (2009) Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-tolead Bioorg Med Chem Lett 19(3):962-966
15. Williams R, Zhou Y, Niswender CM, Luo Q, Conn PJ, Lindsley CW, Hopkins CR (2010) Re-exploration of the PHCCC Scaffold: Discovery of improved positive allosteric modulators of mGluR4. ACS Chem Neurosci 1(6):411-419. doi:10.1021/cn9000318
16. Todeschini R, Consonni V (2000) Handbook of Molecular Descriptors, vol 11. Methods Princ. Med Chem, Wiley-VCH
17. Hansch C, Hoekman D, Leo A, Weininger D, Selassie CD (2002) Chem-bioinformatics: Comparative QSAR at the interface between chemistry and biology. Chem Rev 102(3):783-812
18. Hansch CM, Peyton P, Fujita T, Muir RM (1962) Correlation of biological activity of phenoxyacetic acids with Hammett substituent constants and partition coefficients. Nature 194:178-180
19. Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110(18):5959-5967. doi:10.1021/ja00226a005
20. Klebe G, Abraham U, Mietzner T (1994) Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity. J Med Chem 37 (24):4130-4146. doi:10.1021/jm00050a010
21. Bleckmann A, Meiler J (2003) Epothilones: Quantitative structure activity relations studied by support vector machines and artificial neural networks. QSAR Comb Sci 22(7):719-721
22. Tetko IV, Sushko I, Pandey AK, Zhu H, Tropsha A, Papa E, Oberg T, Todeschini R, Fourches D, Varnek A (2008) Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: Focusing on applicability domain and overfitting by variable selection. J Chem Inf Model 48(9):1733-1746
23. Winkler D (2004) Neural networks as robust tools in drug lead discovery and development. Mol Biotechnol 27(2):139-167
24. Zupan J, Gasteiger J (1993) Neural Networks for Chemists. Weinheim, VCH Verlagsgesellschaft mbH
25. Burton J, Ijjaali I, Barberan O, Petitet F, Vercauteren DP, Michel A (2006) Recursive Partitioning for the Prediction of Cytochromes P450 2D6 and 1A2 Inhibition: Importance of the quality of the dataset. J Med Chem 49(21):6231-6240
26. Hecht D, Cheung M, Fogel GB (2008) QSAR using evolved neural networks for the inhibition of mutant PfDHFR by pyrimethamine derivatives. Biosystems 92(1):10-15. doi:10.1016/ j.biosystems.2007.10.005
27. Hecht D, Fogel GB (2007) High-throughput ligand screening via preclustering and evolved neural networks. IEEE/ACM Trans Comput Biol Bioinform 4(3):476-484. doi :10.1109/ tcbb.2007.1038
28. Butkiewicz M, Mueller R, Selic D, Dawson E, Meiler J (2009) Application of machine learning approaches on quantitative structure activity relationships. Paper presented at the IEEE Symposium on computational intelligence in bioinformatics and computational biology, Nashville
29. Mueller R, Rodriguez AL, Dawson ES, Butkiewicz M, Nguyen TT, Oleszkiewicz S, Bleckmann A, Weaver CD, Lindsley CW, Conn PJ, Meiler J (2010) Identification of metabotropic glutamate receptor subtype 5 potentiators using virtual high-throughput screening. ACS Chem Neurosci 1 (4):288-305. doi:10.1021/ cn9000389
30. Schwab CH, Gasteiger J (2006) ADRIANA.Code, Algorithms for the Encoding of Molecular Structures, Version 2.0, Computerchemie MNG, Program Description
31. Niswender CM, Johnson KA, Luo Q, Ayala JE, Kim C, Conn PJ, Weaver CD (2008) A novel assay of Gi/o-Linked G proteincoupled receptor coupling to potassium channels provides new insights into the pharmacology of the group III metabotropic glutamate receptors. Mol Pharmacol 73(4):1213-1224. doi:10.1124/mol.107.041053
32. Gasteiger J, Rudolph C, Sadowski J (1990) Automatic generation of 3D atomic coordinates for organic molecules. Tetrahedron Comput Methodol 3(6c):537-547
33. Schwab CH (2007) ADRIANA.Code, 20th edn. Molecular Networks GmbH, Erlangen
34. Riedmiller M, Braun H (1992) Rprop-A Fast Adaptive Learning Algorithm. In: International Symposium on Computer and Information Science VII
35. Molecular Operating Environment (MOE) 2010.10 (2010) Chemical Computing Group Inc, 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A 2R7
36. Engers DW, Field JR, Le U, Zhou Y, Bolinger JD, Zamorano R, Blobaum AL, Jones CK, Jadhav S, Weaver CD, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR (2011) Discovery, synthesis, and structure-activity relationship development of a series of N-(4-Acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu4) with CNS exposure in rats. J Med Chem 54(4):1106-1110. doi:10.1021/jm101271s
37. Engers DW, Gentry PR, Williams R, Bolinger JD, Weaver CD, Menon UN, Conn PJ, Lindsley CW, Niswender CM, Hopkins CR (2010) Synthesis and SAR of novel, 4-(phenylsulfamoyl)phenylacetamide mGlu4 positive allosteric modulators (PAMs) identified by functional high-throughput screening (HTS). Bioorg Med Chem Lett 20(17):5175-5178. doi:10.1016/j.bmcl.2010.07.007