Current Therapy and Computational Drug Designing Approaches for Neurodegenerative Diseases -with Focus on Alzheimer’s and Parkinson’s.

Indrani	      Bera

doi:10.2174/1574362413666180312125419

Abstract

Background: Neurodegenerative diseases are age-related ailments which are characterized by progressive neuronal damage and loss. These diseases can be caused by both genetic and environmental factors. Alzheimer’s and Parkinson’s are the most predominant neurodegenerative diseases. Though various research strategies have been employed to eliminate the cause of the disease, till date successful strategies available are symptomatic. Various compounds have been designed against the targets, such as BACE1, acetylcholinesterase, glycogen synthase kinase, muscarinic acetylcholine receptor etc.

Methods: This review consists of information gathered from various research articles and review papers in the concerned field. An attempt was made to identify important findings from these papers. Important in silico techniques used in the identification of drug candidates and newly designed compounds as therapeutics for neurodegenerative diseases were summarized.

Results: Sixty papers were included in this review. A comprehensive overview of computer aided drug designing techniques used aimed at the identification of new drug candidates is provided. Ligand based drug design approaches such as QSAR, virtual screening and pharmacophore have been described. Current therapies used against Alzheimer’s and Parkinson’s have summarized. New compounds against the targets of for Alzheimer’s and Parkinson’s identified by computational screening of compounds have been summarized.

Conclusion: The findings of this review confirm that therapies and current successful strategies for neurodegenerative disease are mainly symptomatic. Current research is mainly focused on preventing the progress of neurodegeneration. Various in silico techniques; ligand-based methods such as QSAR, virtual screening, pharmacophore mapping and structure-based methods such as homology modeling, docking studies have been used to identify therapeutic compounds for Alzheimer’s and Parkinson’s.

Keywords: Neurodegenerative disease, Computer aided drug designing techniques, Alzheimer's, Parkinson's, current therapies, ischemia, Huntington disease.

Graphical Abstract

[1] 
Lardenoije R, Iatrou A, Kenis G, et al. The epigenetics of aging and neurodegeneration. Prog Neurobiol  2015; 131: 21-64.
[http://dx.doi.org/10.1016/j.pneurobio.2015.05.002] [PMID:  26072273] 
[2] 
Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science  2016; 353(6301): 777-83.
[http://dx.doi.org/10.1126/science.aag2590] [PMID:  27540165] 
[3] 
Madabhushi R, Pan L, Tsai LH. DNA damage and its links to neurodegeneration. Neuron  2014; 83(2): 266-82.
[http://dx.doi.org/10.1016/j.neuron.2014.06.034] [PMID:  25033177] 
[4] 
Kovacs GG, Adle-Biassette H, Milenkovic I, Cipriani S, van Scheppingen J, Aronica E. Linking pathways in the developing and aging brain with neurodegeneration. Neuroscience  2014; 269: 152-72.
[http://dx.doi.org/10.1016/j.neuroscience.2014.03.045] [PMID:  24699227] 
[5] 
Leicht H, König HH, Stuhldreher N, et al. Predictors of costs in dementia in a longitudinal perspective. PLoS One  2013; 8(7)e70018
[http://dx.doi.org/10.1371/journal.pone.0070018] [PMID:  23875017] 
[6] 
Park A. How to live 100 years. Time  2010; 175(7): 56-62, 65-66.
[PMID:  20196378] 
[7] 
Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med  2004; 10(Suppl.): S10-7.
[http://dx.doi.org/10.1038/nm1066] [PMID:  15272267] 
[8] 
Contreras-Moreira B, Fitzjohn PW, Bates PA. Comparative modelling: an essential methodology for protein structure prediction in the post-genomic era. Appl Bioinformatics  2002; 1(4): 177-90.
[PMID:  15130836] 
[9] 
Dias R, de Azevedo WF Jr, Walter F. Molecular docking algorithms. Curr Drug Targets  2008; 9(12): 1040-7.
[http://dx.doi.org/10.2174/138945008786949432] [PMID:  19128213] 
[10] 
Venkatachalam CM, Jiang X, Oldfield T, Waldman M. LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites. J Mol Graph Model  2003; 21(4): 289-307.
[http://dx.doi.org/10.1016/S1093-3263(02)00164-X] [PMID:  12479928] 
[11] 
Ewing TJ, Makino S, Skillman AG, Kuntz ID. DOCK 4.0: search strategies for automated molecular docking of flexible molecule databases. J Comput Aided Mol Des  2001; 15(5): 411-28.
[http://dx.doi.org/10.1023/A:1011115820450] [PMID:  11394736] 
[12] 
Morris GM, Goodsell DS, Halliday RS, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem  1998; 19(14): 1639-62.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19:14<1639:AID-JCC10>3.0.CO;2-B] 
[13] 
Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD. Improved protein-ligand docking using GOLD. Proteins  2003; 52(4): 609-23.
[http://dx.doi.org/10.1002/prot.10465] [PMID:  12910460] 
[14] 
Kirkpatrick P. Gliding to success. Nat Rev Drug Discov  2004; 3(4): 299-300.
[http://dx.doi.org/10.1038/nrd1364] 
[15] 
Kubinyi H. QSAR and 3D QSAR in drug design Part 1: methodology. Drug Discov Today  1997; 2(11): 457-67.
[http://dx.doi.org/10.1016/S1359-6446(97)01079-9] 
[16] 
Dudek AZ, Arodz T, Gálvez J. Computational methods in developing quantitative structure-activity relationships (QSAR): a review. Comb Chem High Throughput Screen  2006; 9(3): 213-28.
[http://dx.doi.org/10.2174/138620706776055539] [PMID:  16533155] 
[17] 
Akamatsu M. Current state and perspectives of 3D-QSAR. Curr Top Med Chem  2002; 2(12): 1381-94.
[http://dx.doi.org/10.2174/1568026023392887] [PMID:  12470286] 
[18] 
Cramer RD, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc  1988; 110(18): 5959-67.
[http://dx.doi.org/10.1021/ja00226a005] [PMID:  22148765] 
[19] 
Silverman BD, Platt DE. Comparative molecular moment analysis (CoMMA): 3D-QSAR without molecular superposition. J Med Chem  1996; 39(11): 2129-40.
[http://dx.doi.org/10.1021/jm950589q] [PMID:  8667357] 
[20] 
Verma J, Khedkar VM, Coutinho EC. 3D-QSAR in drug design--a review. Curr Top Med Chem  2010; 10(1): 95-115.
[http://dx.doi.org/10.2174/156802610790232260] [PMID:  19929826] 
[21] 
Hodgson J. ADMET--turning chemicals into drugs. Nat Biotechnol  2001; 19(8): 722-6.
[http://dx.doi.org/10.1038/90761] [PMID:  11479558] 
[22] 
van de Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction paradise. Nat Rev Drug Discov  2003; 2(3): 192-204.
[http://dx.doi.org/10.1038/nrd1032] [PMID:  12612645] 
[23] 
Proudfoot JR. Drugs, leads, and drug-likeness: an analysis of some recently launched drugs. Bioorg Med Chem Lett  2002; 12(12): 1647-50.
[http://dx.doi.org/10.1016/S0960-894X(02)00244-5] [PMID:  12039582] 
[24] 
Wermuth CG, Ganellin CR, Lindberg P, Mitscher LA. Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998). Pure Appl Chem  1998; 70(5): 1129-43.
[http://dx.doi.org/10.1351/pac199870051129] 
[25] 
Ortiz AR, Pisabarro MT, Gago F, Wade RC. Prediction of drug binding affinities by comparative binding energy analysis. J Med Chem  1995; 38(14): 2681-91.
[http://dx.doi.org/10.1021/jm00014a020] [PMID:  7629807] 
[26] 
Reddy AS, Pati SP, Kumar PP, Pradeep HN, Sastry GN. Virtual screening in drug discovery -- a computational perspective. Curr Protein Pept Sci  2007; 8(4): 329-51.
[http://dx.doi.org/10.2174/138920307781369427] [PMID:  17696867] 
[27] 
Bajorath J. Integration of virtual and high-throughput screening. Nat Rev Drug Discov  2002; 1(11): 882-94.
[http://dx.doi.org/10.1038/nrd941] [PMID:  12415248] 
[28] 
Farlow M. A clinical overview of cholinesterase inhibitors in Alzheimer’s disease. Int Psychogeriatr  2002; 14(S1)(Suppl. 1): 93-126.
[http://dx.doi.org/10.1017/S1041610203008688] [PMID:  12636182] 
[29] 
Yiannopoulou KG, Papageorgiou SG. Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disorder  2013; 6(1): 19-33.
[http://dx.doi.org/10.1177/1756285612461679] [PMID:  23277790] 
[30] 
Silvestri R. Boom in the development of non-peptidic β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease. Med Res Rev  2009; 29(2): 295-338.
[http://dx.doi.org/10.1002/med.20132] [PMID:  18651582] 
[31] 
Martinez A, Perez DI. GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer’s disease? J Alzheimers Dis  2008; 15(2): 181-91.
[http://dx.doi.org/10.3233/JAD-2008-15204] [PMID:  18953107] 
[32] 
Yadav HP, Li Y. The development of treatment for Parkinson’s disease. Advances in Parkinson’s Disease  2015; 4(3): 59-78.
[http://dx.doi.org/10.4236/apd.2015.43008] 
[33] 
Dyson SC, Barker RA. Cell-based therapies for Parkinson’s disease. Expert Rev Neurother  2011; 11(6): 831-44.
[http://dx.doi.org/10.1586/ern.11.33] [PMID:  21651331] 
[34] 
Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat  2010; 31(7): 763-80.
[http://dx.doi.org/10.1002/humu.21277] [PMID:  20506312] 
[35] 
Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci  2015; 9: 124.
[http://dx.doi.org/10.3389/fncel.2015.00124] [PMID:  25914621] 
[36] 
Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med  2012; 2(6)a008870
[http://dx.doi.org/10.1101/cshperspect.a008870] [PMID:  22675666] 
[37] 
MS Lima M, F Martins E, Marcia Delattre A, et al.. Motor and non-motor features of Parkinson's disease–a review of clinical and experimental studies. CNS Neurol Disord Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 2012; 11(4): 439-9. 
[38] 
Stefanis L. α-Synuclein in Parkinson’s disease. Cold Spring Harb Perspect Med  2012; 2(2)a009399
[http://dx.doi.org/10.1101/cshperspect.a009399] [PMID:  22355802] 
[39] 
Chaudhuri KR, Rizos A, Sethi KD. Motor and nonmotor complications in Parkinson’s disease: an argument for continuous drug delivery? J Neural Transm (Vienna)  2013; 120(9): 1305-20.
[http://dx.doi.org/10.1007/s00702-013-0981-5] [PMID:  23456290] 
[40] 
Oluigbo CO, Salma A, Rezai AR. Deep brain stimulation for neurological disorders. IEEE Rev Biomed Eng  2012; 5: 88-99.
[http://dx.doi.org/10.1109/RBME.2012.2197745] [PMID:  23231991] 
[41] 
Lunn JS, Sakowski SA, Hur J, Feldman EL. Stem cell technology for neurodegenerative diseases. Ann Neurol  2011; 70(3): 353-61.
[http://dx.doi.org/10.1002/ana.22487] [PMID:  21905078] 
[42] 
Nakata Y, Yasuda T, Mochizuki H. Recent progress in gene therapy for Parkinson’s disease. Curr Mol Med  2012; 12(10): 1311-8.
[http://dx.doi.org/10.2174/156652412803833580] [PMID:  22834832] 
[43] 
Nikolic K, Mavridis L, Djikic T, et al. Drug design for CNS diseases: polypharmacological profiling of compounds using cheminformatic, 3D-QSAR and virtual screening methodologies. Front Neurosci  2016; 10: 265.
[http://dx.doi.org/10.3389/fnins.2016.00265] [PMID:  27375423] 
[44] 
Bautista-Aguilera OM, Samadi A, Chioua M, et al. N-Methyl-N-((1-methyl-5-(3-(1-(2-methylbenzyl)piperidin-4-yl)propoxy)-1H-indol-2-yl)methyl)prop-2-yn-1-amine, a new cholinesterase and monoamine oxidase dual inhibitor. J Med Chem  2014; 57(24): 10455-63.
[http://dx.doi.org/10.1021/jm501501a] [PMID:  25418133] 
[45] 
Nikolic K, Agbaba D, Stark H. Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways. J Taiwan Inst Chem Eng  2015; 46: 15-29.
[http://dx.doi.org/10.1016/j.jtice.2014.09.017] 
[46] 
Vijayan RS, Prabu M, Mascarenhas NM, Ghoshal N. Hybrid structure-based virtual screening protocol for the identification of novel BACE1 inhibitors. J Chem Inf Model  2009; 49(3): 647-57.
[http://dx.doi.org/10.1021/ci800386v] [PMID:  19434899] 
[47] 
Daidone F, Montioli R, Paiardini A, et al. Identification by virtual screening and in vitro testing of human DOPA decarboxylase inhibitors. PLoS One  2012; 7(2)e31610
[http://dx.doi.org/10.1371/journal.pone.0031610] [PMID:  22384042] 
[48] 
Sirci F, Istyastono EP, Vischer HF, et al. Virtual fragment screening: discovery of histamine H3 receptor ligands using ligand-based and protein-based molecular fingerprints. J Chem Inf Model  2012; 52(12): 3308-24.
[http://dx.doi.org/10.1021/ci3004094] [PMID:  23140085] 
[49] 
Geldenhuys WJ, Funk MO, Van der Schyf CJ, Carroll RT. A scaffold hopping approach to identify novel monoamine oxidase B inhibitors. Bioorg Med Chem Lett  2012; 22(3): 1380-3.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.056] [PMID:  22225638] 
[50] 
Yelekçi K, Büyüktürk B, Kayrak N. In silico identification of novel and selective monoamine oxidase B inhibitors. J Neural Transm (Vienna)  2013; 120(6): 853-8.
[http://dx.doi.org/10.1007/s00702-012-0954-0] [PMID:  23242744] 
[51] 
Schmitt KC, Mamidyala S, Biswas S, Dutta AK, Reith ME. Bivalent phenethylamines as novel dopamine transporter inhibitors: evidence for multiple substrate-binding sites in a single transporter. J Neurochem  2010; 112(6): 1605-18.
[http://dx.doi.org/10.1111/j.1471-4159.2010.06583.x] [PMID:  20067583] 
[52] 
Kumar A, Nisha CM, Silakari C, et al. Current and novel therapeutic molecules and targets in Alzheimer’s disease. J Formos Med Assoc  2016; 115(1): 3-10.
[http://dx.doi.org/10.1016/j.jfma.2015.04.001] [PMID:  26220908] 
[53] 
Armstrong RA. What causes alzheimer’s disease? Folia Neuropathol  2013; 51(3): 169-88.
[http://dx.doi.org/10.5114/fn.2013.37702] [PMID:  24114635] 
[54] 
Jacobsen JS, Reinhart P, Pangalos MN. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer’s disease. NeuroRx  2005; 2(4): 612-26.
[http://dx.doi.org/10.1602/neurorx.2.4.612] [PMID:  16489369] 
[55] 
Khan MT, Orhan I, Şenol FS, et al. Cholinesterase inhibitory activities of some flavonoid derivatives and chosen xanthone and their molecular docking studies. Chem Biol Interact  2009; 181(3): 383-9.
[http://dx.doi.org/10.1016/j.cbi.2009.06.024] [PMID:  19596285] 
[56] 
Samadi A, Estrada M, Pérez C, et al. Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer’s disease: synthesis, biological assessment, and molecular modeling. Eur J Med Chem  2012; 57: 296-301.
[http://dx.doi.org/10.1016/j.ejmech.2012.09.030] [PMID:  23078965] 
[57] 
Colotta V, Lenzi O, Catarzi D, et al. 3-Hydroxy-1H-quinazoline-2,4-dione derivatives as new antagonists at ionotropic glutamate receptors: molecular modeling and pharmacological studies. Eur J Med Chem  2012; 54: 470-82.
[http://dx.doi.org/10.1016/j.ejmech.2012.05.036] [PMID:  22704999] 
[58] 
Espinoza-Moraga M, Caballero J, Gaube F, Winckler T, Santos LS. 1-Benzyl-1,2,3,4-tetrahydro-β-carboline as channel blocker of N-methyl-D-aspartate receptors. Chem Biol Drug Des  2012; 79(4): 594-9.
[http://dx.doi.org/10.1111/j.1747-0285.2012.01317.x] [PMID:  22226015] 
[59] 
Ghosh AK, Gemma S, Tang J. β-Secretase as a therapeutic target for Alzheimer’s disease. Neurotherapeutics  2008; 5(3): 399-408.
[http://dx.doi.org/10.1016/j.nurt.2008.05.007] [PMID:  18625451] 
[60] 
Zhu Y, Xiao K, Ma L, et al. Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and β-secretase. Bioorg Med Chem  2009; 17(4): 1600-13.
[http://dx.doi.org/10.1016/j.bmc.2008.12.067] [PMID:  19162488] 
[61] 
Manoharan P, Ghoshal N. Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads. J Biomol Struct Dyn  2017; 1-15.
[PMID:  28617091] 
[62] 
Manoharan P, Ghoshal N. Rationalizing lead optimization by consensus 2D- CoMFA CoMSIA GRIND (3D) QSAR guided fragment hopping in search of γ-secretase inhibitors. Mol Divers  2012; 16(3): 563-77.
[http://dx.doi.org/10.1007/s11030-012-9388-8] [PMID:  22890960] 

Rights & Permissions Print Cite

Article Metrics

37

7

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574362413666180312125419	Print ISSN 1574-3624
Publisher Name Bentham Science Publisher	Online ISSN 2212-389X

Current Signal Transduction Therapy

Current Therapy and Computational Drug Designing Approaches for Neurodegenerative Diseases -with Focus on Alzheimer’s and Parkinson’s.

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract