Exploration of Novel Inhibitors for Bruton’s Tyrosine Kinase by 3D QSAR Modeling and Molecular Dynamics Simulation

• DOI: 10.1371/journal.pone.0147190
• Publication Date: 2016-01-19T20:23:53Z
• Authors: Rohit Bavi; Raj Kumar; Light Choi; Keun Woo Lee
• Keywords: Models, Molecular; 0303 health sciences; Science; Q; R; Quantitative Structure-Activity Relationship; Hydrogen Bonding; Molecular Dynamics Simulation; Protein-Tyrosine Kinases; Molecular Docking Simulation; 03 medical and health sciences; Drug Stability; Drug Design; Agammaglobulinaemia Tyrosine Kinase; Medicine; Humans; Protein Kinase Inhibitors; Research Article; Protein Binding

Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor which expressed in most of the hematopoietic cells and plays an important role many cellular signaling pathways. B cell malignancies are dependent on BCR signaling, thus making BTK efficient therapeutic target. Over last few years, significant efforts have been made order to develop inhibitors treat B-cell malignancies, autoimmunity or allergy/hypersensitivity but limited success has achieved. Here this study, 3D QSAR pharmacophore models were generated for Btk based known IC50 values experimental energy scores with extensive validations. The five features model, Hypo1, includes one hydrogen bond acceptor lipid, donor, three hydrophobic features, highest correlation coefficient (0.98), cost difference (112.87), low RMS (1.68). It was further validated by Fisher’s randomization method test set. well Hypo1 used as query search novel different chemical scaffold using high throughput virtual screening technique. screened compounds sorted applying ADMET properties, Lipinski’s rule molecular docking studies refine retrieved hits. Furthermore, dynamic simulation employed study stability docked conformation investigate binding interactions detail. Several bonds revealed, gatekeeper residues Glu475 Met 477 at hinge region. Overall, suggests that proposed hits may be more effective cancer autoimmune therapy.