title: Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches.
abstract: In our study, a structure-based virtual screening study was conducted to identify potent ITK inhibitors, as ITK is considered to play an important role in the treatment of inflammatory diseases. We developed a structure-based pharmacophore model using the crystal structure (PDB ID: 3MJ2) of ITK complexed with BMS-50944. The most predictive model, SB-Hypo1, consisted of six features: three hydrogen-bond acceptors (HBA), one hydrogen-bond donor (HBD), one ring aromatic (RA), and one hydrophobic (HY). The statistical significance of SB-Hypo1 was validated using wide range of test set molecules and a decoy set. The resulting well-validated model could then be confidently used as a 3D query to screen for drug-like molecules in a database, in order to retrieve new chemical scaffolds that may be potent ITK inhibitors. The hits retrieved from this search were filtered based on the maximum fit value, drug-likeness, and ADMET properties, and the hits that were retained were used in a molecular docking study to find the binding mode and molecular interactions with crucial residues at the active site of the protein. These hits were then fed into a molecular dynamics simulation to study the flexibility of the activation loop of ITK upon ligand binding. This combination of methodologies is a valuable tool for identifying structurally diverse molecules with desired biological activities, and for designing new classes of selective ITK inhibitors.
authors.affiliation: Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Gazha-dong, Jinju, 660-701, Republic of Korea.
authors.forename: Chandrasekaran
authors.initials: C
authors.lastname: Meganathan
authors.forename: Sugunadevi
authors.initials: S
authors.lastname: Sakkiah
authors.forename: Yuno
authors.initials: Y
authors.lastname: Lee
authors.forename: Jayavelu Venkat
authors.initials: JV
authors.lastname: Narayanan
authors.forename: Keun Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D001549:Benzamides / Q000737:chemistry*; D001665:Binding Sites; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D001549:Benzamides; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase