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Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

De-Novo Ligand Design against Mutated Huntington Gene by Ligand-based Pharmacophore Modeling Approach

Author(s): Anum Munir*, Shaukat I. Malik* and Khalid A. Malik

Volume 16, Issue 2, 2020

Page: [134 - 144] Pages: 11

DOI: 10.2174/1573409915666181207104437

Price: $65

Abstract

Background: Huntington's disease is characterized by three side effects, including motor disturbances, psychiatric elements, and intellectual weakness. The onset for HD has nonlinear converse associations with the number of repeat sequences of the polyglutamine mutations, so that younger patients have a tendency for longer repeats length. This HD variation is because of the development of a polyglutamine (CAG) repeats in the exon 1 of the Huntingtin protein.

Methods: In the present study, a few derivatives utilized as a part of the treatment of HD, are used to create the pharmacophore model and based on the features of the pharmacophore model; an attempt is made to design the de-novo drug for the HD protein. HD protein structure was built and docked with the novel ligand, based on shared feature pharmacophore model, through a ligand-based pharmacophore modeling approach.

Results: The novel ligand contains 1 HBAs, 2 HBDs, and 2 aromatic rings. It fulfills all the properties of certain drug-likeness rules, non-toxic in nature. In the docked complex, the common interactive amino acids identified are SER 1035, ALA 1062, MET 1068, LEU 1031, and THR 1036, which confirmed the validity and stability of a ligand molecule to be used as a drug in the treatment of Huntington’s disease.

Conclusion: A novel ligand can be used in clinical trials as a drug molecule against the mutations of HD gene and in laboratory procedures for efficacy analysis.

Keywords: Docking, hereditary, huntington's, pharmacophore, neurodegenerative, modeling approach.

Graphical Abstract

[1]
Roos, R.A. Huntington’s disease: a clinical review. Orphanet J. Rare Dis., 2010, 5, 40.
[http://dx.doi.org/10.1186/1750-1172-5-40] [PMID: 21171977 ]
[2]
Bruyn, G.W. untington’s chorea: historical, clinical and laboratory synopsis. In:. Handbook of Clinical Neurology, Elsevier: Amsterdam. 1968, 6, pp. 298-378.
[3]
Zoghbi, H.Y.; Orr, H.T.; Patterson, M.C.; Firth, H.V.; Deputy, D.C.H.; Dashe, J.F. Huntington disease: Genetics and pathogenesis 2014.
[4]
Paulsen, J.S.; Ready, R.E.; Hamilton, J.M.; Mega, M.S.; Cummings, J.L. Neuropsychiatric aspects of Huntington’s disease. J. Neurol. Neurosurg. Psychiatry, 2001, 71(3), 310-314.
[http://dx.doi.org/10.1136/jnnp.71.3.310] [PMID: 11511702 ]
[5]
Caine, E.D.; Shoulson, I. Psychiatric syndromes in Huntington’s disease. Am. J. Psychiatry, 1983, 140(6), 728-733.
[http://dx.doi.org/10.1176/ajp.140.6.728] [PMID: 6221669 ]
[6]
Cummings, J.L. Behavioral and psychiatric symptoms associated with Huntington’s disease.In: Behavioral Neurology of movements disorders; Raven Press: New York, 1995.
[7]
Folstein, S.E.; Folstein, M.F. Psychiatric features of Huntington’s disease: recent approaches and findings. Psychiatr. Dev., 1983, 1(2), 193-205.
[PMID: 6232607 ]
[8]
Shiwach, R. Psychopathology in Huntington’s disease patients. Acta Psychiatr. Scand., 1994, 90(4), 241-246.
[http://dx.doi.org/10.1111/j.1600-0447.1994.tb01587.x] [PMID: 7831992 ]
[9]
Morris, M. Psychiatric aspects of Huntington's disease: In Harper PS, ed. Huntington’s disease. WB Saunders: London 1991, 22, pp. 81-126.
[10]
Paulsen, J.S.; Langbehn, D.R.; Stout, J.C.; Aylward, E.; Ross, C.A.; Nance, M.; Guttman, M.; Johnson, S.; MacDonald, M.; Beglinger, L.J.; Duff, K.; Kayson, E.; Biglan, K.; Shoulson, I.; Oakes, D.; Hayden, M. Predict-HD investigators and coordinators of the huntington study group. detection of huntington’s disease decades before diagnosis: the Predict-HD study. J. Neurol. Neurosurg. Psychiatry, 2008, 79(8), 874-880.
[http://dx.doi.org/10.1136/jnnp.2007.128728] [PMID: 18096682 ]
[11]
Gusella, J.F.; MacDonald, M.E. Huntington’s disease: CAG genetics expands neurobiology. Curr. Opin. Neurobiol., 1995, 5(5), 656-662.
[http://dx.doi.org/10.1016/0959-4388(95)80072-7] [PMID: 8580718 ]
[12]
Paulson, H.L.; Fischbeck, K.H. Trinucleotide repeats in neurogenetic disorders. Annu. Rev. Neurosci., 1996, 19, 79-107.
[http://dx.doi.org/10.1146/annurev.ne.19.030196.000455] [PMID: 8833437 ]
[13]
Evans, S.J.; Douglas, I.; Rawlins, M.D.; Wexler, N.S.; Tabrizi, S.J.; Smeeth, L. Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. J. Neurol. Neurosurg. Psychiatry, 2013, 84(10), 1156-1160.
[http://dx.doi.org/10.1136/jnnp-2012-304636] [PMID: 23482661 ]
[14]
Wexler, N.S. Huntington’s disease: advocacy driving science. Annu. Rev. Med., 2012, 63, 1-22.
[http://dx.doi.org/10.1146/annurev-med-050710-134457] [PMID: 22248319 ]
[15]
Myers, R.H. Huntington’s disease genetics. NeuroRx, 2004, 1(2), 255-262.
[http://dx.doi.org/10.1602/neurorx.1.2.255] [PMID: 15717026 ]
[16]
Bates, G. Huntingtin aggregation and toxicity in Huntington’s disease. Lancet, 2003, 361(9369), 1642-1644.
[http://dx.doi.org/10.1016/S0140-6736(03)13304-1] [PMID: 12747895 ]
[17]
Gusella, J.F.; Wexler, N.S.; Conneally, P.M.; Naylor, S.L.; Anderson, M.A.; Tanzi, R.E.; Watkins, P.C.; Ottina, K.; Wallace, M.R.; Sakaguchi, A.Y. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature, 1983, 306(5940), 234-238.
[http://dx.doi.org/10.1038/306234a0] [PMID: 6316146 ]
[18]
The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 1993, 72(6), 971-983.
[http://dx.doi.org/10.1016/0092-8674(93)90585-E] [PMID: 8458085 ]
[19]
Duyao, M.; Ambrose, C.; Myers, R.; Novelletto, A.; Persichetti, F.; Frontali, M.; Folstein, S.; Ross, C.; Franz, M.; Abbott, M. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat. Genet., 1993, 4(4), 387-392.
[http://dx.doi.org/10.1038/ng0893-387] [PMID: 8401587 ]
[20]
Frank, S. Treatment of Huntington’s disease. Neurotherapeutics, 2014, 11(1), 153-160.
[http://dx.doi.org/10.1007/s13311-013-0244-z] [PMID: 24366610 ]
[21]
Pidgeon, C.; Rickards, H. The pathophysiology and pharmacological treatment of Huntington disease. Behav. Neurol., 2013, 26(4), 245-253.
[http://dx.doi.org/10.1155/2013/705373] [PMID: 22713409 ]
[22]
Armstrong, M.J.; Miyasaki, J.M. American Academy of Neurology. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology, 2012, 79(6), 597-603.
[http://dx.doi.org/10.1212/WNL.0b013e318263c443] [PMID: 22815556 ]
[23]
Paleacu, D. Tetrabenazine in the treatment of Huntington’s disease. Neuropsychiatr. Dis. Treat., 2007, 3(5), 545-551.
[PMID: 19381278 ]
[24]
Bagchi, S.P. Differential interactions of phencyclidine with tetrabenazine and reserpine affecting intraneuronal dopamine. Biochem. Pharmacol., 1983, 32(19), 2851-2856.
[http://dx.doi.org/10.1016/0006-2952(83)90388-X] [PMID: 6626259 ]
[25]
Bonelli, R.M.; Wenning, G.K. Pharmacological management of Huntington’s disease: an evidence-based review. Curr. Pharm. Des., 2006, 12(21), 2701-2720.
[http://dx.doi.org/10.2174/138161206777698693] [PMID: 16842168 ]
[26]
Voet, A.; Qing, X.; Lee, X.Y.; De Raeymaecker, J.; Tame, J.; Zhang, K.; De Maeyer, M. Pharmacophore modeling: advances, limitations, and current utility in drug discovery. J. Receptor Ligand Channel Res., 2014, 81
[http://dx.doi.org/10.2147/JRLCR.S46843]
[27]
Geppert, T.D.; Lipsky, P.E. Antigen presentation at the inflammatory site. Crit. Rev. Immunol., 1989, 9(4), 313-362.
[PMID: 2679663 ]
[28]
Rebhan, M.; Chalifa-Caspi, V.; Prilusky, J.; Lancet, D. GeneCards: a novel functional genomics compendium with automated data mining and query reformulation support. Bioinformatics, 1998, 14(8), 656-664.
[http://dx.doi.org/10.1093/bioinformatics/14.8.656] [PMID: 9789091 ]
[29]
Marchler-Bauer, A.; Lu, S.; Anderson, J.B.; Chitsaz, F.; Derbyshire, M.K.; DeWeese-Scott, C.; Fong, J.H.; Geer, L.Y.; Geer, R.C.; Gonzales, N.R.; Gwadz, M.; Hurwitz, D.I.; Jackson, J.D.; Ke, Z.; Lanczycki, C.J.; Lu, F.; Marchler, G.H.; Mullokandov, M.; Omelchenko, M.V.; Robertson, C.L.; Song, J.S.; Thanki, N.; Yamashita, R.A.; Zhang, D.; Zhang, N.; Zheng, C.; Bryant, S.H. CDD: a Conserved Domain Database for the functional annotation of proteins. Nucleic Acids Res., 2011, 39(Database issue), D225-D229.
[http://dx.doi.org/10.1093/nar/gkq1189] [PMID: 21109532 ]
[30]
Wiederstein, M.; Sippl, M.J. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins.. Nucleic Acids Res., 2007, 35(Web Server issue), W407-10.
[http://dx.doi.org/10.1093/nar/gkm290] [PMID: 17517781 ]
[31]
Bowie, J.U.; Lüthy, R.; Eisenberg, D. A method to identify protein sequences that fold into a known three-dimensional structure. Science, 1991, 253(5016), 164-170.
[http://dx.doi.org/10.1126/science.1853201] [PMID: 1853201 ]
[32]
Colovos, C.; Yeates, T.O. Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci., 1993, 2(9), 1511-1519.
[http://dx.doi.org/10.1002/pro.5560020916] [PMID: 8401235 ]
[33]
Lazareno, S.; Birdsall, N.J. Estimation of competitive antagonist affinity from functional inhibition curves using the Gaddum, Schild and Cheng-Prusoff equations. Br. J. Pharmacol., 1993, 109(4), 1110-1119.
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb13737.x] [PMID: 8401922 ]
[34]
Wolber, G.; Langer, T. LigandScout: Automated Pharmacophore Model Creation www.uibk.ac.at/pharmazie/phchem/camd/publications/poster_gerhard.pdf
[35]
Pollastri, M.P. Overview of the Rule of Five.Current Protocols in Pharmacology; John Wiley & Sons, Inc., 2001.
[36]
Munir, A.; Azam, S.; Ali, S.; Mehmood, A.; Hussain Shah, A.; Khan, M.S.; Fazal, S. Repurposing of Modified Alpidem and Propoxyphene to Cure AURKA, BCAS1, GNAS and MLH1 Gene Mutations in Colorectal Cancer. Drug Designing: Open Access, 2017, 06(01)
[http://dx.doi.org/10.4172/2169-0138.1000141]
[37]
Khedkar, S.A.; Malde, A.K.; Coutinho, E.C.; Srivastava, S. Pharmacophore modeling in drug discovery and development: an overview. Med. Chem., 2007, 3(2), 187-197.
[http://dx.doi.org/10.2174/157340607780059521] [PMID: 17348856 ]
[38]
Kandakatla, N.; Ramakrishnan, G. Ligand Based Pharmacophore Modeling and Virtual Screening Studies to Design Novel HDAC2 Inhibitors. Adv. Bioinforma., 2014, 2014812148
[http://dx.doi.org/10.1155/2014/812148] [PMID: 25525429 ]
[39]
Munir, A.; Azam, S.; Mehmood, A. Structure-Based Pharmacophore Modeling, Virtual Screening and Molecular docking for the Treatment of ESR1 Mutations in Breast Cancer. Drug Designing: Open Access, 2016, 05(03)
[http://dx.doi.org/10.4172/2169-0138.1000137]
[40]
Yang, S.Y. Pharmacophore modeling and applications in drug discovery: challenges and recent advances. Drug Discov. Today, 2010, 15(11-12), 444-450.
[http://dx.doi.org/10.1016/j.drudis.2010.03.013] [PMID: 20362693 ]
[41]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014 ]
[42]
Veber, DF.; Johnson, SR.; Cheng, HY.; Smith, BR.; Ward, KW.; Kopple, KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem, 2002, 6,45(12), 2615-23.
[http://dx.doi.org/10.1021/jm020017n]
[43]
Egan, W.J.; Merz, K.M., Jr; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem., 2000, 43(21), 3867-3877.
[http://dx.doi.org/10.1021/jm000292e] [PMID: 11052792 ]
[44]
Muegge, I.; Heald, S.L.; Brittelli, D. Simple selection criteria for drug-like chemical matter. J. Med. Chem., 2001, 44(12), 1841-1846.
[http://dx.doi.org/10.1021/jm015507e] [PMID: 11384230 ]
[45]
Datta, D. Protein-ligand interactions: docking, design and protein conformational change California Institute of Technology, 2003.http://thesis.library.caltech.edu/1086/
[46]
Haseeb, M.; Vaqar, S.; Fazal, S.; Khalil, A. Ligand based pharmacophore development for colorectal cancer drugs. Prof. Med. J., 2014, 21(5)http://theprofesional.com/article/vol-21-no-05/prof-2566.pdf
[47]
Datta, D. Protein-ligand interactions: Docking, design and protein conformational change; California Institute of Technology, 2003, pp. 1-53.

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