{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:12:29Z","timestamp":1760238749811,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T00:00:00Z","timestamp":1598400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A significant percentage of Duchenne muscular dystrophy (DMD) cases are caused by premature termination codon (PTC) mutations in the dystrophin gene, leading to the production of a truncated, non-functional dystrophin polypeptide. PTC-suppressing compounds (PTCSC) have been developed in order to restore protein translation by allowing the incorporation of an amino acid in place of a stop codon. However, limitations exist in terms of efficacy and toxicity. To identify new compounds that have PTC-suppressing ability, we selected and clustered existing PTCSC, allowing for the construction of a common pharmacophore model. Machine learning (ML) and deep learning (DL) models were developed for prediction of new PTCSC based on known compounds. We conducted a search of the NCI compounds database using the pharmacophore-based model and a search of the DrugBank database using pharmacophore-based, ML and DL models. Sixteen drug compounds were selected as a consensus of pharmacophore-based, ML, and DL searches. Our results suggest notable correspondence of the pharmacophore-based, ML, and DL models in prediction of new PTC-suppressing compounds.<\/jats:p>","DOI":"10.3390\/molecules25173886","type":"journal-article","created":{"date-parts":[[2020,8,26]],"date-time":"2020-08-26T09:56:58Z","timestamp":1598435818000},"page":"3886","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prediction of Premature Termination Codon Suppressing Compounds for Treatment of Duchenne Muscular Dystrophy Using Machine Learning"],"prefix":"10.3390","volume":"25","author":[{"given":"Kate","family":"Wang","sequence":"first","affiliation":[{"name":"MAP program, University of California San Diego (UCSD), La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eden L.","family":"Romm","sequence":"additional","affiliation":[{"name":"Curematch Inc., 6440 Lusk Blvd, Suite D206, San Diego, CA 92121, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina L.","family":"Kouznetsova","sequence":"additional","affiliation":[{"name":"San Diego Supercomputer Center, University of California San Diego (UCSD), La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor F.","family":"Tsigelny","sequence":"additional","affiliation":[{"name":"Curematch Inc., 6440 Lusk Blvd, Suite D206, San Diego, CA 92121, USA"},{"name":"San Diego Supercomputer Center, University of California San Diego (UCSD), La Jolla, CA 92093, USA"},{"name":"Dept. of Neurosciences, University of California San Diego (UCSD), La Jolla, CA 92093, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1152\/physrev.00028.2001","article-title":"Function and Genetics of Dystrophin and Dystrophin-Related Proteins in Muscle","volume":"82","author":"Blake","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/sj.embor.7400221","article-title":"Duchenne muscular dystrophy and dystrophin: Pathogenesis and opportunities for treatment","volume":"5","author":"Nowak","year":"2004","journal-title":"EMBO Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.molmed.2012.09.008","article-title":"Sense from nonsense: Therapies for premature stop codon diseases","volume":"18","author":"Bidou","year":"2012","journal-title":"Trends Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1128\/AAC.46.5.1546-1549.2002","article-title":"30S Ribosomal Subunit Assembly Is a Target for Inhibition by Aminoglycosides in Escherichia coli","volume":"46","author":"Mehta","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/ana.20052","article-title":"Readthrough of dystrophin stop codon mutations induced by aminoglycosides","volume":"55","author":"Howard","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1021\/jm801640k","article-title":"Development of Novel Aminoglycoside (NB54) with Reduced Toxicity and Enhanced Suppression of Disease-Causing Premature Stop Mutations","volume":"52","author":"Nudelman","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1074\/jbc.M113.533588","article-title":"Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: A strategy for the treatment of genetic diseases","volume":"289","author":"Shulman","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev-genom-091212-153527","article-title":"Therapeutics based on stop codon readthrough","volume":"15","author":"Keeling","year":"2014","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41598-017-01093-9","article-title":"Aminoglycosides, but not PTC124 (Ataluren), rescue nonsense mutations in the leptin receptor and in luciferase reporter genes","volume":"7","author":"Bolze","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"444","DOI":"10.3109\/10409238.2012.694846","article-title":"Suppression of premature termination codons as a therapeutic approach","volume":"47","author":"Keeling","year":"2012","journal-title":"Crit. Rev. Biochem. Mol. Boil."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1093\/jb\/mvg203","article-title":"Negamycin Restores Dystrophin Expression in Skeletal and Cardiac Muscles of mdx Mice","volume":"134","author":"Arakawa","year":"2003","journal-title":"J. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s00109-015-1364-1","article-title":"A flow cytometry-based reporter assay identifies macrolide antibiotics as nonsense mutation read-through agents","volume":"94","author":"Caspi","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"237","DOI":"10.3233\/JND-170230","article-title":"Analysis of Azithromycin Monohydrate as a Single or a Combinatorial Therapy in a Mouse Model of Severe Spinal Muscular Atrophy","volume":"4","author":"Osman","year":"2017","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1136\/gut.2008.169805","article-title":"Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons","volume":"59","author":"Zilberberg","year":"2009","journal-title":"Gut"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1261\/rna.060236.116","article-title":"The nucleoside analog clitocine is a potent and efficacious readthrough agent","volume":"23","author":"Friesen","year":"2017","journal-title":"RNA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1164\/rccm.201601-0154OC","article-title":"Discovery of Clinically Approved Agents That Promote Suppression of Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations","volume":"194","author":"Mutyam","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1093\/hmg\/dds223","article-title":"Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy","volume":"21","author":"Kayali","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1084\/jem.20081940","article-title":"Nonaminoglycoside compounds induce readthrough of nonsense mutations","volume":"206","author":"Du","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1038\/mt.2013.150","article-title":"A New Series of Small Molecular Weight Compounds Induce Read Through of All Three Types of Nonsense Mutations in the ATM Gene","volume":"21","author":"Du","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1750-1172-7-58","article-title":"Rescue of nonsense mutations by amlexanox in human cells","volume":"7","author":"Beghyn","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s10020-018-0024-7","article-title":"Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons","volume":"24","author":"Dabrowski","year":"2018","journal-title":"Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/j.ymthe.2017.07.014","article-title":"Quantitative Antisense Screening and Optimization from Exon 51 Skipping in Duchenne Muscular Dystrophy","volume":"25","author":"Echigoya","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.ejmech.2018.03.065","article-title":"Discovery of N-hydroxy-3-alkoxybenzamides as direct acid sphingomyelinase inhibitors using a ligand-based pharmacophore model","volume":"151","author":"Yang","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_24","unstructured":"Bruns, D. (2018). The Roads that Lead to Cell Migration Modulators: Ligand-based drug Design of Chemokine Receptor Ligands. [Ph.D. Thesis, ETH Zurich]."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Li, B., Kang, X., Zhao, D., Zou, Y., Huang, X., Wang, J., and Zhang, C. (2019). Machine Learning Models Combined with Virtual Screening and Molecular Docking to Predict Human Topoisomerase I Inhibitors. Molecules, 24.","DOI":"10.3390\/molecules24112107"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"036003","DOI":"10.1088\/1478-3975\/ab6819","article-title":"Deep-learning- and pharmacophore-based prediction of RAGE inhibitors","volume":"17","author":"Huang","year":"2020","journal-title":"Phys. Boil."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wolska, N., Boncler, M., Polak, D., Wzorek, J., Przygodzki, T., Gapi\u0144ska, M., Watala, C., and Rozalski, M. (2019). Adenosine Receptor Agonists Exhibit Anti-Platelet Effects and the Potential to Overcome Resistance to P2Y12 Receptor Antagonists. Molecules, 25.","DOI":"10.3390\/molecules25010130"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"44","DOI":"10.7324\/JAPS.2012.2407","article-title":"Radical scavenging activities of the leaf extracts and a flavonoid glycoside isolated from Cineraria abyssinica Sch. Bip. Exa. Rich","volume":"02","author":"Sintayehu","year":"2012","journal-title":"J. Appl. Pharm. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.imlet.2014.12.006","article-title":"Immunotoxicological effects of streptozotocin and alloxan: In vitro and in vivo studies","volume":"163","author":"Diab","year":"2015","journal-title":"Immunol. Lett."},{"key":"ref_31","first-page":"012152","article-title":"Antioxidant activity, phenol and flavonoid content, and formulation cream of Stevia rebaudiana Bert","volume":"1217","author":"Kusmita","year":"2019","journal-title":"J. Physics: Conf. Ser."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6104","DOI":"10.1128\/AAC.01326-12","article-title":"Structure-Activity Relationships among the Kanamycin Aminoglycosides: Role of Ring I Hydroxyl and Amino Groups","volume":"56","author":"Salian","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1093\/jac\/dku550","article-title":"Aminoglycoside-modifying enzymes determine the innate susceptibility to aminoglycoside antibiotics in rapidly growing mycobacteria","volume":"70","author":"Maurer","year":"2015","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1080\/14756360409162451","article-title":"Effects of Some Antibiotics on Human Erythrocyte 6-Phosphogluconate Dehydrogenase: Anin vitroandin vivoStudy","volume":"19","author":"Erat","year":"2004","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"a025387","DOI":"10.1101\/cshperspect.a025387","article-title":"Tetracycline Antibiotics and Resistance","volume":"6","author":"Grossman","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1021\/ci990307l","article-title":"Prediction of Physicochemical Parameters by Atomic Contributions","volume":"39","author":"Wildman","year":"1999","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2174\/138161207779313731","article-title":"Aminoglycoside-induced ototoxicity","volume":"13","author":"Selimoglu","year":"2007","journal-title":"Curr. Pharm. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1758-2946-6-23","article-title":"A rotation-translation invariant molecular descriptor of partial charges and its use in ligand-based virtual screening","volume":"6","author":"Berenger","year":"2014","journal-title":"J. Chemin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/8904_2013_270","article-title":"Aminoglycoside-Induced Premature Stop Codon Read-Through of Mucopolysaccharidosis Type I Patient Q70X and W402X Mutations in Cultured Cells","volume":"13","author":"Kamei","year":"2013","journal-title":"JIMD Reports"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9:e52611","DOI":"10.7554\/eLife.52611","article-title":"Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides","volume":"9","author":"Wangen","year":"2020","journal-title":"eLife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1021\/cb700100n","article-title":"A Steric Block in Translation Caused by the Antibiotic Spectinomycin","volume":"2","author":"Borovinskaya","year":"2007","journal-title":"ACS Chem. Boil."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.tibs.2018.06.011","article-title":"How Macrolide Antibiotics Work","volume":"43","author":"Mankin","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrm4069","article-title":"Ribosome profiling reveals the what, when, where and how of protein synthesis","volume":"16","author":"Brar","year":"2015","journal-title":"Nat. Rev. Mol. Cell Boil."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1073\/pnas.1517541113","article-title":"Molecular mechanism of viomycin inhibition of peptide elongation in bacteria","volume":"113","author":"Holm","year":"2016","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1073\/pnas.1216691110","article-title":"Structural basis for potent inhibitory activity of the antibiotic tigecycline during protein synthesis","volume":"110","author":"Jenner","year":"2013","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4889","DOI":"10.1128\/AAC.48.12.4889-4891.2004","article-title":"Effects of a Number of Classes of 50S Inhibitors on Stop Codon Readthrough during Protein Synthesis","volume":"48","author":"Thompson","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1128\/AAC.04809-14","article-title":"Activity of Eravacycline against Enterobacteriaceae and Acinetobacter baumannii, Including Multidrug-Resistant Isolates, from New York City","volume":"59","author":"Abdallah","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/jcc.21707","article-title":"PaDEL-descriptor: An open source software to calculate molecular descriptors and fingerprints","volume":"32","author":"Yap","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_49","unstructured":"Whitten, I.H., Frank, E., and Hall, M.A. (2016). Appendix B: The WEKA Workbench. Data Mining, Morgan Kauffmann. [4th ed.]."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1145\/3022670.2976746","article-title":"TensorFlow: Learning functions at scale","volume":"51","author":"Abadi","year":"2016","journal-title":"ACM SIGPLAN Not."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/3886\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:06:51Z","timestamp":1760177211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/3886"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,26]]},"references-count":50,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["molecules25173886"],"URL":"https:\/\/doi.org\/10.3390\/molecules25173886","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2020,8,26]]}}}