Pharmacophore Design for Anti-inflammatory Agent Targeting Interleukin-2 Inducible Tyrosine Kinase (Itk)

Meganathan, C.; Thangapandian, Sundarapandian; Sundaraganesan, N.; Kim, Hyong-Ha; Kim, Yong-Seong; Lee, Keun Woo

doi:10.5012/bkcs.2010.31.11.3333

Bulletin of the Korean Chemical Society

2010

DOI: 10.5012/bkcs.2010.31.11.3333

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Pharmacophore Design for Anti-inflammatory Agent Targeting Interleukin-2 Inducible Tyrosine Kinase (Itk)

C. Meganathan¹,

Sundarapandian Thangapandian²,

N. Sundaraganesan³

et al.

Abstract: A three dimensional pharmacophore model was generated for the molecules which are responsible for anti-inflammatory activities targeting Interleukin-2 inducible tyrosine kinase (Itk). 16 structurally diverse molecules were selected as training set to generate the hypotheses using Discovery Studio v2.1. The best hypothesis, Hypo1, comprises two hydrogen bond acceptor (HBA), one hydrophobic aromatic (HA), one ring aromatic (RA) and shows high cost difference (63.71), high correlation coefficient (0.97) as well a… Show more

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Cited by 3 publications

(1 citation statement)

References 27 publications

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“…Initially receptor was prepared by applying CHARMm force field using DS. 40 After protein preparation, binding site of the protein has to be identified to dock the small molecules. The active site of protein can be represented as binding site; it is a set of points on a grid that lie in a cavity.…”

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confidence: 99%

Macromolecular Docking Simulation to Identify Binding Site of FGB1 for Antifungal Compounds

Soundararajan¹,

Sakkiah²,

Sivanesan³

et al. 2011

Bulletin of the Korean Chemical Society

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Fusarium oxysporum, an important pathogen that mainly causes vascular or fusarium wilt disease which leads to economic loss. Disruption of gene encoding a heterotrimeric G-protein-β-subunit (FGB1), led to decreased intracellular cAMP levels, reduced pathogenicity, colony morphology, and germination. The plant defense protein, Nicotiana alata defensin (NaD1) displays potent antifungal activity against a variety of agronomically important filamentous fungi. In this paper, we performed a molecular modeling and docking studies to find vital amino acids which can interact with various antifungal compounds using Discovery Studio v2.5 and GRAMM-X, respectively. The docking results from FGB1-NaD1 and FGB1-antifungal complexes, revealed the vital amino acids such as His64, Trp65, Ser194, Leu195, Gln237, Phe238, Val324 and Asn326, and suggested that the anidulafungin is a the good antifungal compound.The predicted interaction can greatly assist in understanding structural insights for studying the pathogen and host-component interactions.

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mentioning

confidence: 99%

Macromolecular Docking Simulation to Identify Binding Site of FGB1 for Antifungal Compounds

Soundararajan¹,

Sakkiah²,

Sivanesan³

et al. 2011

Bulletin of the Korean Chemical Society

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Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches

et al. 2012

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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.

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Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes

Gajjar

Anuradha

2020

CDDT

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Background: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. Methods: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Results and Conclusion: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

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Pharmacophore Design for Anti-inflammatory Agent Targeting Interleukin-2 Inducible Tyrosine Kinase (Itk)

Cited by 3 publications

References 27 publications

Macromolecular Docking Simulation to Identify Binding Site of FGB1 for Antifungal Compounds

Macromolecular Docking Simulation to Identify Binding Site of FGB1 for Antifungal Compounds

Discovery of potent inhibitors for interleukin-2-inducible T-cell kinase: structure-based virtual screening and molecular dynamics simulation approaches

Combiphore (Structure and Ligand Based Pharmacophore) - Approach for the Design of GPR40 Modulators in the Management of Diabetes

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