Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches
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Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approachesChandrasekaran MeganathanSugunadevi SakkiahYuno LeeJayavelu Venkat NarayananKeun Woo LeeOriginal PaperDOI:
10.-012-1536-7Cite this article as: Meganathan, C., Sakkiah, S., Lee, Y. et al. J Mol Model (5. doi:10.-012-1536-7
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.FigureA structure-based pharmacophore model was developed, using a fully resolved crystal structure, in order to identify novel virtual lead compounds for use in ITK inhibitor designITKInflammatoryLigandScoutVirtual screeningMolecular dockingITKInterleukin-2-inducible T-cell kinaseSB_Hypo1Structure-based hypothesisPTKProtein tyrosine kinasePHPleckstrin homologySH3Src homology3SH2Src homology2DSDiscovery Studio v.2.5HBAHydrogen-bond acceptorHBDHydrogen-bond donorHYHydrophobicRRing aromaticEFEnrichment factorGHGoodness of hitADMETAbsorption, distribution, metabolism, excretion, and toxicityBBBBlood–brain barrierMDMolecular dynamicsRMSDRoot mean square deviation (40 kb)Table S1Statistical parameters obtained when screening the decoy set using SB_Hypo1 (DOC 40 kb) (46 kb)Table S2Score function values for the reference compound and the database hits, as well as the molecular interactions of these compounds with the critical residues at the active site of ITK (DOC 45 kb) (38 kb)Table S3Details of the molecular dynamics simulation system (DOC 37 kb) (526 kb)Fig. S1Initial pharmacophore model developed using LigandScout (JPEG 526 kb) (4.3 mb)High-resolution image (TIFF 4452 kb) (401 kb)Fig. S2a Chemical features of the SB_Hypo1 pharmacophore model of ITK inhibitors. b Comparison of SB_Hypo1 with a ligand-based pharmacophore model developed previously. Color code for SB_Hypo1: green HBA, magenta HBD, blue HY, orange RA; color code for the ligand-based pharmacophore model: dark green HBA, dark blue HY, yellow RA (JPEG 400 kb) (JPEG 400 kb) (2.8 mb)High-resolution image (TIFF 2891 kb) (164 kb)Fig. S3a The complex of ITK and BMS-509744 (the reference compound) overlaid onto the GOLD docking conformation (shown in cyan) ; RMSD = 0.98 ?. b Molecular interactions of BMS-509744 with the active site of ITK (JPEG 579 kb) (JPEG 163 kb) (1.2 mb)High-resolution image (TIFF 2891 kb) (579 kb)Fig. S4Pharmacophore overlay and molecular interaction of database hits a Pharmacophore overlay of CD_01889, b Molecular interaction of CD_01889, c Pharmacophore overlay of JFD_01598, d Molecular interaction of JFD_01598 [color code: pink – CD_01889, gold – JFD_01598 and residues are in elemental color] (JPEG 579 kb) (4 mb)High-resolution image (TIFF 4093 kb) (368 kb)Fig. S5Pharmacophore overlay and molecular interaction of database hit and binding with reference compound a Compound 11513 overlaid onto the b molecular interactions of compound 11513 with the active site of ITK, c binding modes of all of the database hits and the reference compound (BMS-509744) with ITK (JPEG 368 kb) (2.4 mb)High-resolution image (TIFF 2468 kb) (256 kb)Fig. S6RMSD plots for five structures modeled in MD simulations. The RMSDs of the Cα atoms with respect to their initial coordinates were measured over the course of five MD simulations. Apo, BMS, CD_01889, JFD_01598, and compound 11513 are represented by blue, red, green, dark blue, and violet lines, respectively. (JPEG 256 kb) (1.7 mb)High-resolution image (TIFF 1743 kb) (672 kb)Fig. S7Comparison of representative protein structures of a the apo form, b BMS-509744, c CD_01889, d compound 11513 (JPEG 671 kb) (4.9 mb)High-resolution image (TIFF 5066 kb) (387 kb)Fig. S8Comparison of the representative protein structure and the secondary structure of compound JFD_01598 (JPEG 387 kb) (2.7 mb)High-resolution image (TIFF 2717 kb)1.Smith CIE, Islam TC, Mattsson PT, Mohamed AJ, Nore BF, Vihinen M (2001) The Tec family of cytoplasmic tyrosine kinases: mammalian Btk, Bmx, Itk, Tec, Txk and homologs in other species. BioEssays 23(5):436–446. doi:
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Chandrasekaran Meganathan1Sugunadevi Sakkiah1Yuno Lee1Jayavelu Venkat Narayanan2Keun Woo Lee11.Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS)Gyeongsang National University (GNU)JinjuRepublic of Korea2.Department of Oral and Maxillofacial SurgeryRagas Dental College and HospitalChennaiIndia
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