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

Medicinal Chemistry Research

Volumn 23, Issue 8, 2014, Pages 3705-3713

  Bhayye, Sagar S ^a   Roy, Kunal ^b   Saha, Achintya ^a  

^a UNIVERSITY OF CALCUTTA   (India)

^b JADAVPUR UNIVERSITY   (India)

Author keywords

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

Indexed keywords

ANTIPARKINSON AGENT; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; GUANOSINE TRIPHOSPHATE; JANUS KINASE 3; LEUCINE RICH REPEAT KINASE 2; LEUCINE RICH REPEAT KINASE 2 INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DRUG DATABASE; DRUG DESIGN; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SCREENING; ENZYME ACTIVITY; GENE MUTATION; HYDROGEN BOND; HYDROPHOBICITY; LRKK2 GENE; MODEL; MOLECULAR DOCKING; MUTATOR GENE; PARKINSON DISEASE; PATHOGENESIS; PHARMACOPHORE; PROTEIN DOMAIN;

EID: 84904419662     PISSN: 10542523     EISSN: 15548120     Source Type: Journal    
DOI: 10.1007/s00044-014-0955-7     Document Type: Article

References (47)

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
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/EP2011/059009
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/EP2011/069696
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
5. Chan B, Estrada A, Sweeney Z, Mciver EG (2011) Pyrazolopyridines as inhibitors of the kinase LRRK2. WO Patent App. PCT/GB2011/050937
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
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
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
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
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
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 (Pubitemid 23262844)
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
13. Dachsel JC, Farrer MJ (2010) LRRK2 and Parkinson disease. Arch Neurol 67(5):542. doi:10.1001/archneurol.2010.79
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
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
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
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
18. Discovery studio 2.5 (2009) Accelrys Inc., San Diego
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 (Pubitemid 24062616)
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
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
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
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
24. Glide 5.5 (2009) Schrödinger. LLC, New York
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 (Pubitemid 43125977)
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
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 (Pubitemid 26152973)
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
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 (Pubitemid 40635354)
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 (Pubitemid 350162903)
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
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
33. Lewis PA (2009) The function of ROCO proteins in health and disease. Biol Cell 101(3):183-191. doi:10.1042/BC20080053
34. LigPrep 2.3 (2009) Schrödinger. LLC, New York
35. Protein Preparation Wizard (2009) Schrödinger. LLC, New York
36. PyMOL 1.3 (2010) Schrödinger. LLC, New York
37. QikProp 3.2 (2009) Schrödinger. LLC, New York
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
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
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
41. Singh R, Balupuri A, Sobhia ME (2013a) Development of 3Dpharmacophore 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
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
43. Smellie A, Teig SL, Towbin P (1995) Poling: promoting conformational variation. J Comput Chem 16(2):171-187. doi:10.1002/jcc.540160205
44. SYBYL 7.1 (2005) Tripose Inc., St. Louis
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
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
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