Front Pharmacol. 2020 Jan 29;10:1653. doi: 10.3389/fphar.2019.01653. eCollection 2019.
A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer's Disease.
Frontiers in pharmacology
Soo Youn Lee, Min-Young Song, Dain Kim, Chaewon Park, Da Kyeong Park, Dong Geun Kim, Jong Shin Yoo, Young Hye Kim
Affiliations
Affiliations
- Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Cheongju, South Korea.
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, South Korea.
PMID: 32063857
PMCID: PMC7000455 DOI: 10.3389/fphar.2019.01653
Abstract
Numerous clinical trials of drug candidates for Alzheimer's disease (AD) have failed, and computational drug repositioning approaches using omics data have been proposed as effective alternative approaches to the discovery of drug candidates. However, little multi-omics data is available for AD, due to limited availability of brain tissues. Even if omics data exist, systematic drug repurposing study for AD has suffered from lack of big data, insufficient clinical information, and difficulty in data integration on account of sample heterogeneity derived from poor diagnosis or shortage of qualified post-mortem tissue. In this study, we developed a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) based on inverse associations between disease- and drug-induced gene and protein perturbation patterns, incorporating pharmacogenomic knowledge. We constructed a Drug-induced Gene Perturbation Signature Database (DGPSD) comprised of 61,019 gene signatures perturbed by 1,520 drugs from the Connectivity Map (CMap) and the L1000 CMap. Drugs were classified into three DRPCs (High, Intermediate, and Low) according to DRPSs that were calculated using drug- and disease-induced gene perturbation signatures from DGPSD and The Cancer Genome Atlas (TCGA), respectively. The DRPS/C method was evaluated using the area under the ROC curve, with a prescribed drug list from TCGA as the gold standard. Glioblastoma had the highest AUC. To predict anti-AD drugs, DRPS were calculated using DGPSD and AD-induced gene/protein perturbation signatures generated from RNA-seq, microarray and proteomic datasets in the Synapse database, and the drugs were classified into DRPCs. We predicted 31 potential anti-AD drug candidates commonly belonged to high DRPCs of transcriptomic and proteomic signatures. Of these, four drugs classified into the nervous system group of Anatomical Therapeutic Chemical (ATC) system are voltage-gated sodium channel blockers (bupivacaine, topiramate) and monamine oxidase inhibitors (selegiline, iproniazid), and their mechanism of action was inferred from a potential anti-AD drug perspective. Our approach suggests a shortcut to discover new efficacy of drugs for AD.
Copyright © 2020 Lee, Song, Kim, Park, Park, Kim, Yoo and Kim.
Keywords: Alzheimer disease; computational drug repositioning; drug discovery; drug repositioning; proteomics; proteotranscriptomics; system based approach; transcriptomics
References
- Nat Commun. 2018 Jan 30;9(1):327 - PubMed
- EMBO Mol Med. 2016 Jun 01;8(6):595-608 - PubMed
- Nat Commun. 2018 Sep 3;9(1):3561 - PubMed
- Nat Commun. 2017 Jul 12;8:16022 - PubMed
- FEBS Lett. 2006 Jan 9;580(1):107-14 - PubMed
- Dis Chest. 1954 May;25(5):573-9 - PubMed
- Neuropsychopharmacology. 2015 Feb;40(3):650-7 - PubMed
- Endocrinology. 2012 Sep;153(9):4401-11 - PubMed
- Lancet Neurol. 2010 Apr;9(4):413-24 - PubMed
- Alzheimers Dement. 2018 Apr;14(4):535-562 - PubMed
- Proc Natl Acad Sci U S A. 2011 May 10;108(19):8059-64 - PubMed
- N Engl J Med. 1997 Apr 24;336(17):1216-22 - PubMed
- J Med Chem. 2012 Oct 11;55(19):8483-92 - PubMed
- FEBS Lett. 2011 Jun 23;585(12):1801-6 - PubMed
- Pharmacology. 2011;87(3-4):121-9 - PubMed
- J Biol Chem. 2008 Dec 5;283(49):33902-10 - PubMed
- Biogerontology. 2014 Dec;15(6):547-57 - PubMed
- Curr Top Med Chem. 2012;12(20):2275-82 - PubMed
- Trends Cardiovasc Med. 2010 Jan;20(1):16-21 - PubMed
- Front Pharmacol. 2016 Oct 18;7:340 - PubMed
- Hum Genet. 2017 Oct;136(10):1341-1351 - PubMed
- Curr Top Med Chem. 2012;12(20):2163-76 - PubMed
- PLoS One. 2016 Dec 22;11(12):e0168812 - PubMed
- Arch Gen Psychiatry. 1987 May;44(5):427-33 - PubMed
- Drug Discov Today. 2014 Nov;19(11):1751-1756 - PubMed
- Bioinformatics. 2014 Feb 15;30(4):523-30 - PubMed
- Front Neurosci. 2018 Jun 26;12:419 - PubMed
- Cell. 2017 Nov 30;171(6):1437-1452.e17 - PubMed
- Neurosci Lett. 2004 Jan 30;355(3):169-72 - PubMed
- Mol Med Rep. 2014 May;9(5):1533-41 - PubMed
- Sci Rep. 2019 Sep 19;9(1):13548 - PubMed
- Psychother Psychosom. 2014;83(2):89-105 - PubMed
- Oncogene. 2018 Jan 18;37(3):403-414 - PubMed
- Nat Neurosci. 2010 Jul;13(7):812-8 - PubMed
- Mol Cell. 2012 Aug 24;47(4):535-46 - PubMed
- PLoS One. 2011;6(12):e28025 - PubMed
- PLoS One. 2014 May 23;9(5):e98185 - PubMed
- Local Reg Anesth. 2018 Aug 08;11:35-44 - PubMed
- Curr Aging Sci. 2018;11(2):77-89 - PubMed
- Cell. 2016 Feb 11;164(4):603-15 - PubMed
- J Clin Psychopharmacol. 2008 Jun;28(3):296-301 - PubMed
- BMC Cancer. 2019 Jun 25;19(1):628 - PubMed
- BMC Neurol. 2016 Nov 22;16(1):236 - PubMed
- Sci Adv. 2019 Mar 20;5(3):eaav0316 - PubMed
- J Forensic Sci. 1995 Nov;40(6):1100-2 - PubMed
- Nat Commun. 2017 Sep 18;8(1):573 - PubMed
- Cell Signal. 2004 Feb;16(2):187-200 - PubMed
- J Alzheimers Dis Rep. 2018 Dec 14;2(1):213-218 - PubMed
- Life Sci. 1989;45(6):525-31 - PubMed
- Neurobiol Aging. 2000 Mar-Apr;21(2):343-8 - PubMed
- Clin Transl Sci. 2018 Mar;11(2):147-152 - PubMed
- Mol Cancer Ther. 2014 Jul;13(7):1929-1941 - PubMed
- Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21830-5 - PubMed
- J Biol Chem. 2011 Mar 11;286(10):8106-16 - PubMed
- Neuron. 2012 Jan 26;73(2):374-90 - PubMed
- Lancet Neurol. 2012 Oct;11(10):868-77 - PubMed
- Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082 - PubMed
- Brief Bioinform. 2011 Jul;12(4):303-11 - PubMed
- Science. 2006 Sep 29;313(5795):1929-35 - PubMed
- J Med Chem. 2013 Nov 14;56(21):8377-88 - PubMed
Publication Types