title: Target-based drug discovery for [Formula: see text]-globin disorders: drug target prediction using quantitative modeling with hybrid functional Petri nets.
abstract: Recent molecular studies provide important clues into treatment of [Formula: see text]-thalassemia, sickle-cell anaemia and other [Formula: see text]-globin disorders revealing that increased production of fetal hemoglobin, that is normally suppressed in adulthood, can ameliorate the severity of these diseases. In this paper, we present a novel approach for drug prediction for [Formula: see text]-globin disorders. Our approach is centered upon quantitative modeling of interactions in human fetal-to-adult hemoglobin switch network using hybrid functional Petri nets. In accordance with the reverse pharmacology approach, we pose a hypothesis regarding modulation of specific protein targets that induce [Formula: see text]-globin and consequently fetal hemoglobin. Comparison of simulation results for the proposed strategy with the ones obtained for already existing drugs shows that our strategy is the optimal as it leads to highest level of [Formula: see text]-globin induction and thereby has potential beneficial therapeutic effects on [Formula: see text]-globin disorders. Simulation results enable verification of model coherence demonstrating that it is consistent with qPCR data available for known strategies and/or drugs.
authors.affiliation: * Department of Applied Mathematics and Computer Science, Eastern Mediterranean University, Famagusta, North Cyprus, Mersin 10, Turkey.
authors.forename: Mani
authors.initials: M
authors.lastname: Mehraei
authors.affiliation: * Department of Applied Mathematics and Computer Science, Eastern Mediterranean University, Famagusta, North Cyprus, Mersin 10, Turkey.
authors.forename: Rza
authors.initials: R
authors.lastname: Bashirov
authors.affiliation: † Department of Biological Sciences, Eastern Mediterranean University, Famagusta, North Cyprus, Mersin 10, Turkey.
authors.forename: Şükrü
authors.initials: Ş
authors.lastname: Tüzmen
mesh_terms: D000328:Adult; D000631:Aminopyridines / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D055808:Drug Discovery / Q000379:methods*; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D006453:Hemoglobinopathies / Q000188:drug therapy* / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors; D008962:Models, Theoretical; D058990:Molecular Targeted Therapy / Q000379:methods*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012097:Repressor Proteins; D055755:SOXD Transcription Factors / Q000037:antagonists & inhibitors; D019821:Simvastatin / Q000494:pharmacology; D055544:beta-Globins / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: C000625520:ACY-957; D000631:Aminopyridines; C486563:BCL11A protein, human; D001549:Benzamides; D002087:Butyrates; D002352:Carrier Proteins; D006873:Hydroquinones; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D011725:Pyridines; D011804:Quinolines; D012097:Repressor Proteins; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D055544:beta-Globins; C080774:erythroid Kruppel-like factor; D055545:gamma-Globins; C118739:entinostat; D005319:Fetal Hemoglobin; D019821:Simvastatin; C074677:2,2-dimethylbutyric acid; C018855:2-tert-butylhydroquinone; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: -thalassemia; Reverse pharmacology; drug discovery; fetal-to-adult hemoglobin switch network; hybrid functional Petri net; quantitative modeling; sickle-cell anaemia