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

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

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

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

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

Chan B, Estrada A, Sweeney Z, Mciver EG (2011) Pyrazolopyridines as inhibitors of the kinase LRRK2. WO Patent App. PCT/GB2011/050937

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

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

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

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

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

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

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

Dachsel JC, Farrer MJ (2010) LRRK2 and Parkinson disease. Arch Neurol 67(5):542. doi: 10.1001/archneurol.2010.79

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

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

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

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

Discovery studio 2.5 (2009) Accelrys Inc., San Diego

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

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

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

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

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

Glide 5.5 (2009) Schrödinger. LLC, New York

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

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

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

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

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

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

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

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

Lewis PA (2009) The function of ROCO proteins in health and disease. Biol Cell 101(3):183–191. doi: 10.1042/BC20080053

LigPrep 2.3 (2009) Schrödinger. LLC, New York

Protein Preparation Wizard (2009) Schrödinger. LLC, New York

PyMOL 1.3 (2010) Schrödinger. LLC, New York

QikProp 3.2 (2009) Schrödinger. LLC, New York

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

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

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

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

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

Smellie A, Teig SL, Towbin P (1995) Poling: promoting conformational variation. J Comput Chem 16(2):171–187. doi: 10.1002/jcc.540160205

SYBYL 7.1 (2005) Tripose Inc., St. Louis

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

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

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