Background and Purpose In this study, we demonstrate the use of Molecular topology (MT) in an Alzheimer’s disease (AD) drug discovery program. MT uses and expands upon the principles governing the molecular connectivity theory of numerically characterizing molecular structures, in the present case, active anti-AD drugs/agents, using topological descriptors to build models. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy. Experimental Approach We used MT to include multiple bioactive properties that allows for the identification of multi-functional single agent compounds, in this case, the dual functions of β-amyloid (Aβ) -lowering and anti-oligomerization. Using this technology, we identified and designed novel compounds in chemical classes unrelated to current anti-AD agents that exert dual Aβ lowering and anti-Aβ oligomerization activities in animal models of AD. AD is a multifaceted disease with different pathological features. Conclusion and Implications Our study, for the first time, demonstrated that MT can provide novel strategy for discovering drugs with Aβ lowering and anti-aggregation dual activities for AD.
References
[1]
Alzheimer’s Association (2006) Fact Sheet: Alzheimer’s Disease.
[2]
Alzheimer’s Study Group (2010) A National Alzheimer’s Strategic Plan: The Report of the Alzheimer’s Study Group.
[3]
Braak H, Braak E (1997) Staging of Alzheimer-related cortical destruction. Int.Psychogeriatr 9 Suppl 1257–261. doi: 10.1017/s1041610297004973
[4]
Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, et al. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360: 672–674. doi: 10.1038/360672a0
[5]
Emilien G, Maloteaux JM, Beyreuther K, Masters CL (2000) Alzheimer disease: mouse models pave the way for therapeutic opportunities. Arch Neurol 57: 176–181. doi: 10.1001/archneur.57.2.176
[6]
Morgan D (2005) Mechanisms of A beta plaque clearance following passive A beta immunization. Neurodegener Dis 2: 261–6. doi: 10.1159/000090366
[7]
Walsh DM, Selkoe DJ (2007) A beta oligomers - a decade of discovery. J Neurochem 101: 1172–1184. doi: 10.1111/j.1471-4159.2006.04426.x
[8]
Dickson DW, Crystal HA, Bevona C, Honer W, Vincent I, et al. (1995) Correlations of synaptic and pathological markers with cognition of the elderly. Neurobiol.Aging 16: 285–298. doi: 10.1016/0197-4580(95)00013-5
[9]
Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, et al. (2003) Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 62: 1087–1095.
[10]
De Leon MJ, Mosconi L, Blennow K, DeSanti S, Zinkowski R, et al. (2007) Imaging and CSF studies in the preclinical diagnosis of Alzheimer’s disease. Ann N Y Acad Sci 1097: 114–145. doi: 10.1196/annals.1379.012
[11]
Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ (2002) Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans 30: 552–557. doi: 10.1042/bst0300552
[12]
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, et al. (2007) Natural Oligomers of the Alzheimer Amyloid-{beta} Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway. J Neurosci 27: 2866–2875. doi: 10.1523/jneurosci.4970-06.2007
[13]
Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, et al. (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440: 352–7. doi: 10.1038/nature04533
[14]
Walsh DM, Townsend M, Podlisny MB, Shankar GM, Fadeeva JV, et al. (2005) Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation. J Neurosci 25: 2455–2462. doi: 10.1523/jneurosci.4391-04.2005
[15]
Boado RJ, Zhang Y, Zhang Y, Xia CF, Pardridge WM (2007) Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. Bioconjug Chem 18: 447–455. doi: 10.1021/bc060349x
[16]
Giacobini E, Becker RE (2007) One hundred years after the discovery of Alzheimer’s disease. A turning point for therapy? J Alzheimers Dis 12: 37–52.
[17]
Galvez J, Garcia-Domenech R, de Julian-Ortiz JV, Soler R (1995) Topological approach to drug design. J Chem Inf Comput Sci 35: 272–284. doi: 10.1021/ci00024a017
[18]
Garcia-Domenech R, Galvez J, de Julian-Ortiz JV, Pogliani L (2008) Some new trends in chemical graph theory. Chem Rev 108: 1127–1169. doi: 10.1021/cr0780006
[19]
Kier LB, Hall LH (1986) Molecular Connectivity in Structure–Activity Analysis, John Wiley &Sons.
[20]
Dudek AZ, Arodz T, Galvez J (2006) Computational methods in developing quantitative structure-activity relationships (QSAR): a review. Comb Chem High Throughput Screen 9: 213–228. doi: 10.2174/138620706776055539
[21]
Jasinski P, Welsh B, Galvez J, Land D, Zwolak P, et al. (2008) A novel quinoline, MT477: suppresses cell signaling through Ras molecular pathway, inhibits PKC activity, and demonstrates in vivo anti-tumor activity against human carcinoma cell lines. Invest New Drugs 26: 223–232. doi: 10.1007/s10637-007-9096-x
[22]
Randic M (1975) On characterization of molecular branching. Journal of the American Chemical Society 97: 6609–6615. doi: 10.1021/ja00856a001
[23]
Hosoya H (1971) Topological index. A newly proposed quantity characterizing the topological nature of structural isomers of saturated hydrocarbons. Bull Chem Soc Jpn 44: 2332–2339. doi: 10.1246/bcsj.44.2332
[24]
Todeschini R, Consonni V (2000) Handbook of Molecular Descriptors. Wiley-VCH, Methods and Principles in Medicinal Chemistry 11.
[25]
Galvez J, Garcia-Domenech R, de Gregorio AC, de Julian-Ortiz JV, Popa L (1996) Pharmacological distribution diagrams: a tool for de novo drug design. J Mol Graph 14: 272–276. doi: 10.1016/s0263-7855(96)00081-1
[26]
Wang J, Ho L, Zhao Z, Seror I, Humala N, et al. (2006) Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer’s disease. FASEB J 20: 2313–2320. doi: 10.1096/fj.06-6281com
[27]
Klein WL (2002) A[beta] toxicity in Alzheimer’s disease: globular oligomers (ADDLs) as new vaccine and drug targets. Neurochemistry International 41: 345–352. doi: 10.1016/s0197-0186(02)00050-5
[28]
Bitan G, Lomakin A, Teplow DB (2001) Amyloid beta -Protein Oligomerization. Prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins. J Biol Chem 276: 35176–35184. doi: 10.1074/jbc.m102223200
[29]
Ono K, Condron MM, Ho L, Wang J, Zhao W, et al. (2008) Effects of Grape Seed-derived Polyphenols on Amyloid {beta}-Protein Self-assembly and Cytotoxicity. J Biol Chem 283: 32176–32187. doi: 10.1074/jbc.m806154200
[30]
Wang J, Ho L, Zhao W, Ono K, Rosensweig C, et al. (2008) Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci 28: 6388–6392. doi: 10.1523/jneurosci.0364-08.2008
[31]
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, et al. (1996) Correlative Memory Deficits, Abeta Elevation, and Amyloid Plaques in Transgenic Mice. Science 274: 99–103. doi: 10.1126/science.274.5284.99
[32]
Wang J, Ho L, Qin W, Rocher AB, Seror I, et al. (2005) Caloric restriction attenuates beta-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB J 19: 659–661. doi: 10.1096/fj.04-3182fje
[33]
Vollers SS, Teplow DB, Bitan G (2005) Determination of Peptide oligomerization state using rapid photochemical crosslinking. Methods Mol Biol 299: 11–18. doi: 10.1385/1-59259-874-9:011
