Medicinal Chemistry Research

, Volume 23, Issue 8, pp 3705–3713 | Cite as

Exploring structural requirement, pharmacophore modeling, and de novo design of LRRK2 inhibitors using homology modeling approach

Original Research

Abstract

A mutation in the gene, encoding leucine rich repeat kinase 2 (LRRK2), is a genetic cause of Parkinson’s disease (PD). LRRK2 is a dimeric multidomain protein, largely regulates guanosine triphosphate (GTP). G2019S and I2020T, the mutation encodes in the kinase domain of LRRK2 increase the GTPase activity, are the important regulators in pathogenesis of PD. To design potent LRRK2 inhibitors, pharmacophore modeling approach was employed with a wide chemical diversity of compound’s database. The best hypothesis consists of hydrogen-bond acceptor and donor as well as hydrophobic aliphatic and ring aromatic features. The model was validated by the test and decoy sets followed by Fischer’s randomization test. The validated model was used to screen the database of compounds, which were designed through de novo approach. Homology model of the kinase domain of LRRK2 was built initially using the crystal structure of Janus kinase 3. The designed molecules were further screened for ADMET properties, and ligand–receptor interaction of top hits was analyzed by molecular docking studies to explore potent LRRK2 inhibitors.

Keywords

Pharmacophore De novo drug design Homology modeling Leucine rich repeat kinase 2 Parkinson’s disease 

Supplementary material

44_2014_955_MOESM1_ESM.pdf (337 kb)
Supplementary material 1 (PDF 336 kb)
44_2014_955_MOESM2_ESM.docx (1.5 mb)
Supplementary material 2 (DOCX 1508 kb)

References

  1. Anand VS, Reichling LJ, Lipinski K, Stochaj W, Duan W, Kelleher K, Pungaliya P, Brown EL, Reinhart PH, Somberg R (2009) Investigation of leucine rich repeat kinase 2. FEBS J 276(2):466–478. doi:10.1111/j.1742-4658.2008.06789.x CrossRefPubMedGoogle Scholar
  2. Baker-Glenn C, Burdick DJ, Chambers M, Chan BK, Chen H, Estrada A, Gunzner JL, Shore D, Sweeney ZK, Wang S (2011a) Aminopyrimidine derivatives as LRRK2 modulators. WO Patent App. PCT/EP2011/059009Google Scholar
  3. Baker-Glenn C, Burdick DJ, Chambers M, Chan BK, Chen H, Estrada A, Sweeney ZK (2011b) Pyrazole aminopyrimidine derivatives as LRRK2 modulators. WO Patent App. PCT/EP2011/069696Google Scholar
  4. Cereto-Massagué A, Guasch L, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S (2012) DecoyFinder: an easy-to-use python GUI application for building target-specific decoy sets. Bioinformatics 28(12):1661–1662. doi:10.1093/bioinformatics/bts249 CrossRefPubMedGoogle Scholar
  5. Chan B, Estrada A, Sweeney Z, Mciver EG (2011) Pyrazolopyridines as inhibitors of the kinase LRRK2. WO Patent App. PCT/GB2011/050937Google Scholar
  6. Chan BK, Estrada AA, Chen H, Atherall J, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Dominguez SL, Drummond J (2012) Discovery of a highly selective, brain-penetrant aminopyrazole LRRK2 inhibitor. ACS Med Chem Lett 4(1):85–90. doi:10.1021/ml3003007 PubMedCentralCrossRefPubMedGoogle Scholar
  7. Chen H, Chan BK, Drummond J, Estrada AA, Gunzner Toste J, Liu X, Liu Y, Moffat J, Shore D, Sweeney ZK (2012) Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling. J Med Chem 55(11):5536–5545. doi:10.1021/jm300452p CrossRefPubMedGoogle Scholar
  8. Choi HG, Zhang J, Deng X, Hatcher JM, Patricelli MP, Zhao Z, Alessi DR, Gray NS (2012) Brain penetrant LRRK2 inhibitor. ACS Med Chem Lett 3(8):658–662. doi:10.1021/ml300123a PubMedCentralCrossRefPubMedGoogle Scholar
  9. Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA, Williams JM, Day JE (2010) Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol 400(3):413–433. doi:10.1016/j.jmb.2010.05.020 CrossRefPubMedGoogle Scholar
  10. Cole C, Barber JD, Barton GJ (2008) The Jpred 3 secondary structure prediction server. Nucleic Acids Res 36(suppl 2):W197–W201. doi:10.1093/nar/gkn238 PubMedCentralCrossRefPubMedGoogle Scholar
  11. Colovos C, Yeates TO (1993) Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 2(9):1511–1519. doi:10.1002/pro.5560020916 PubMedCentralCrossRefPubMedGoogle Scholar
  12. Cookson MR (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson’s disease. Nat Rev Neurosci 11(12):791–797. doi:10.1038/nrn2935 CrossRefPubMedGoogle Scholar
  13. Dachsel JC, Farrer MJ (2010) LRRK2 and Parkinson disease. Arch Neurol 67(5):542. doi:10.1001/archneurol.2010.79 CrossRefPubMedGoogle Scholar
  14. Deng X, Dzamko N, Prescott A, Davies P, Liu Q, Yang Q, Lee JD, Patricelli MP, Nomanbhoy TK, Alessi DR (2011) Characterization of a selective inhibitor of the Parkinson’s disease kinase LRRK2. Nat Chem Biol 7(4):203–205. doi:10.1038/nchembio.538 PubMedCentralCrossRefPubMedGoogle Scholar
  15. Deng X, Choi HG, Buhrlage SJ, Gray NS (2012) Leucine-rich repeat kinase 2 inhibitors: a patent review (2006–2011). Expert Opin Ther Pat 22(12):1415–1426. doi:10.1517/13543776.2012.729041 CrossRefPubMedGoogle Scholar
  16. Dexter DT, Jenner P (2013) Parkinson’s disease: from pathology to molecular disease mechanisms. Free Radic Biol Med. 62:132–144. doi:10.1016/j.freeradbiomed.2013.01.018 CrossRefPubMedGoogle Scholar
  17. Dhoke GV, Gangwal RP, Sangamwar AT (2012) A combined ligand and structure based approach to design potent PPAR-alpha agonists. J Mol Struct 1028:22–30. doi:10.1016/j.molstruc.2012.06.032 CrossRefGoogle Scholar
  18. Discovery studio 2.5 (2009) Accelrys Inc., San DiegoGoogle Scholar
  19. Enslein K, Gombar VK, Blake BW (1994) Use of SAR in computer-assisted prediction of carcinogenicity and mutagenicity of chemicals by the TOPKAT program. Mutat Res 305(1):47–61. doi:10.1016/0027-5107(94)90125-2 CrossRefPubMedGoogle Scholar
  20. Estrada AA, Liu X, Baker-Glenn C, Beresford A, Burdick DJ, Chambers M, Chan BK, Chen H, Ding X, DiPasquale AG (2012) Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem 55(22):9416–9433. doi:10.1021/jm301020q CrossRefPubMedGoogle Scholar
  21. Eswar N, Eramian D, Webb B, Shen MY, Sali A (2008) Protein structure modeling with MODELLER. Structural Proteomics. Springer, London, pp 145–159. doi:10.1007/978-1-60327-058-8_8 CrossRefGoogle Scholar
  22. Gandhi PN, Chen SG, Wilson-Delfosse AL (2009) Leucine rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson’s disease. J Neurosci Res 87(6):1283–1295. doi:10.1002/jnr.21949 PubMedCentralCrossRefPubMedGoogle Scholar
  23. Gilsbach BK, Ho FY, Vetter IR, van Haastert PJ, Wittinghofer A, Kortholt A (2012) Roco kinase structures give insights into the mechanism of Parkinson disease-related leucine-rich-repeat kinase 2 mutations. Proc Natl Acad Sci USA 109(26):10322–10327. doi:10.1073/pnas.1203223109 PubMedCentralCrossRefPubMedGoogle Scholar
  24. Glide 5.5 (2009) Schrödinger. LLC, New YorkGoogle Scholar
  25. Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O’Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 15(2):223–232. doi:10.1093/hmg/ddi439 CrossRefPubMedGoogle Scholar
  26. Greggio E, Cookson MR (2009) Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro 1(1):13–24. doi:10.1042/AN20090007 CrossRefGoogle Scholar
  27. Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38. doi:10.1016/0263-7855(96)00018-5 CrossRefPubMedGoogle Scholar
  28. Kare P, Bhat J, Sobhia ME (2013) Structure-based design and analysis of MAO-B inhibitors for Parkinson’s disease: using in silico approaches. Mol Divers 17(1):111–122. doi:10.1007/s11030-012-9420-z CrossRefPubMedGoogle Scholar
  29. Kristam R, Gillet VJ, Lewis RA, Thorner D (2005) Comparison of conformational analysis techniques to generate pharmacophore hypotheses using catalyst. J Chem Inf Model 45(2):461–476. doi:10.1021/ci049731z CrossRefPubMedGoogle Scholar
  30. Larkin M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H, Valentin F, Wallace I, Wilm A, Lopez R (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23(21):2947–2948. doi:10.1093/bioinformatics/btm404 CrossRefPubMedGoogle Scholar
  31. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26(2):283–291. doi:10.1107/S0021889892009944 CrossRefGoogle Scholar
  32. Lee BD, Dawson VL, Dawson TM (2012) Leucine-rich repeat kinase 2 (LRRK2) as a potential therapeutic target in Parkinson’s disease. Trends Pharmacol Sci 33(7):365–373. doi:10.1016/j.tips.2012.04.001 PubMedCentralCrossRefPubMedGoogle Scholar
  33. Lewis PA (2009) The function of ROCO proteins in health and disease. Biol Cell 101(3):183–191. doi:10.1042/BC20080053 CrossRefPubMedGoogle Scholar
  34. LigPrep 2.3 (2009) Schrödinger. LLC, New YorkGoogle Scholar
  35. Protein Preparation Wizard (2009) Schrödinger. LLC, New YorkGoogle Scholar
  36. PyMOL 1.3 (2010) Schrödinger. LLC, New YorkGoogle Scholar
  37. QikProp 3.2 (2009) Schrödinger. LLC, New YorkGoogle Scholar
  38. Ramachandran G, Ramakrishnan C, Sasisekharan V (1963) Stereochemistry of polypeptide chain configurations. J Mol Biol 7:95. doi:10.1016/S0022-2836(63)80023-6 CrossRefPubMedGoogle Scholar
  39. Reith AD, Bamborough P, Jandu K, Andreotti D, Mensah L, Dossang P, Choi HG, Deng X, Zhang J, Alessi DR (2012) GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substituent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett 22(17):5625–5629. doi:10.1016/j.bmcl.2012.06.104 PubMedCentralCrossRefPubMedGoogle Scholar
  40. Rudenko IN, Chia R, Cookson MR (2012) Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson’s disease? BMC Med 10(1):20. doi:10.1186/1741-7015-10-20 PubMedCentralCrossRefPubMedGoogle Scholar
  41. Singh R, Balupuri A, Sobhia ME (2013a) Development of 3D-pharmacophore model followed by successive virtual screening, molecular docking and ADME studies for the design of potent CCR2 antagonists for inflammation-driven diseases. Mol Simul 39(1):49–58. doi:10.1080/08927022.2012.701743 CrossRefGoogle Scholar
  42. Singh U, Gangwal RP, Prajapati R, Dhoke GV, Sangamwar AT (2013b) 3D QSAR pharmacophore-based virtual screening and molecular docking studies to identify novel matrix metalloproteinase 12 inhibitors. Mol Simul 39(5):385–396. doi:10.1080/08927022.2012.731506 CrossRefGoogle Scholar
  43. Smellie A, Teig SL, Towbin P (1995) Poling: promoting conformational variation. J Comput Chem 16(2):171–187. doi:10.1002/jcc.540160205 CrossRefGoogle Scholar
  44. SYBYL 7.1 (2005) Tripose Inc., St. LouisGoogle Scholar
  45. Tsika E, Moore DJ (2012) Mechanisms of LRRK2-mediated neurodegeneration. Curr Neurol Neurosci Rep 12(3):251–260. doi:10.1007/s11910-012-0265-8 CrossRefPubMedGoogle Scholar
  46. Yuan Y, Pei J, Lai L (2011) LigBuilder 2: a practical de novo drug design approach. J Chem Inf Model 51(5):1083–1091. doi:10.1021/ci100350u CrossRefPubMedGoogle Scholar
  47. Zhang J, Deng X, Choi HG, Alessi DR, Gray NS (2012) Characterization of TAE684 as a potent LRRK2 kinase inhibitor. Bioorg Med Chem Lett 22(5):1864–1869. doi:10.1016/j.bmcl.2012.01.084 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Chemical TechnologyUniversity of CalcuttaKolkataIndia
  2. 2.Department of Pharmaceutical TechnologyJadavpur UniversityKolkataIndia

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