title: In silico identification of novel IL-1β inhibitors to target protein-protein interfaces.
abstract: Interleukin-1β is a drug target in rheumatoid arthritis and several auto-immune disorders. In this study, a set of 48 compounds with the determined IC50 values were used for QSAR analysis by MOE. The QSAR model was developed by using training set of 41 compounds, based on 12 unique descriptors. Model was validated by predicting the IC50 values for a test set of 7 compounds. A correlation analysis was carried out comparing the statistics of the measured IC50 values with predicted ones. Subsequently, model was used for the screening of a large data set of 7,397,957 compounds obtained from "Drugs Now" category of ZINC database. The activities of those compounds were predicted by developed model. 708,960 compounds that showed best predicted activities were chosen for further studies. Additionally this set of 708,960 compounds was screened by pharmacophore modeling that led to the retrieval of 1809 molecules. Finally docking of 1809 molecules was conducted at the IL-1β receptor binding site using MOE and FRED docking program. Several new compounds were predicted as IL-1β inhibitors in silico. This study provides valuable insight for designing more potent and selective inhibitors for the treatment of inflammatory diseases.
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan. Electronic address: sobia.halim@cemb.edu.pk.
authors.forename: Sobia Ahsan
authors.initials: SA
authors.lastname: Halim
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Jawad
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ilyas
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Zulfiqar
authors.initials: Z
authors.lastname: Mir
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Atif Anwar
authors.initials: AA
authors.lastname: Mirza
authors.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Tayyab
authors.initials: T
authors.lastname: Husnain
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D017472:Receptors, Interleukin-1 / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1
keywords: IL-1β; Molecular docking; Pharmacophore modeling; QSAR; Virtual screening