Target-based drug discovery for [Formula: see text]-globin disorders: drug target prediction using quantitative modeling with hybrid functional Petri nets

• Published in: Journal of bioinformatics and computational biology Vol. 14; no. 5; p. 1650026
• Main Authors: Mehraei, Mani, Bashirov, Rza, Tüzmen, Şükrü
• Format: Journal Article
• Language: English
• Published: England 01-10-2016
• Subjects: Adult; Aminopyridines - pharmacology; Benzamides - pharmacology; beta-Globins - genetics; Butyrates - pharmacology; Carrier Proteins - antagonists & inhibitors; Drug Discovery - methods; Fetal Hemoglobin - genetics; Fetal Hemoglobin - metabolism; gamma-Globins - genetics; gamma-Globins - metabolism; Hemoglobinopathies - drug therapy; Hemoglobinopathies - genetics; Histone Deacetylase 1 - antagonists & inhibitors; Humans; Hydroquinones - pharmacology; Kruppel-Like Transcription Factors - antagonists & inhibitors; Models, Theoretical; Molecular Targeted Therapy - methods; Nuclear Proteins - antagonists & inhibitors; Pyridines - pharmacology; Quinolines - pharmacology; Simvastatin - pharmacology; SOXD Transcription Factors - antagonists & inhibitors; quantitative modeling; thalassemia; drug discovery; fetal-to-adult hemoglobin switch network; sickle-cell anaemia; hybrid functional Petri net; Reverse pharmacology
• ISSN: 1757-6334

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.