title: Receptor-guided 3D-QSAR studies, molecular dynamics simulation and free energy calculations of Btk kinase inhibitors.
abstract: Bruton tyrosine kinase (Btk) plays an important role in B-cell development, differentiation, and signaling. It is also found be in involved in male immunodeficiency disease such as X-linked agammaglobulinemia (XLA). Btk is considered as a potential therapeutic target for treating autoimmune diseases and hematological malignancies.
  
  
  
  In this work, a combined molecular modeling study was performed on a series of thieno [3,2-c] pyridine-4-amine derivatives as Btk inhibitors. Receptor-guided COMFA (q2= 0.574, NOC = 3, r2= 0.924) and COMSIA (q2= 0.646, NOC = 6, r2= 0.971) models were generated based on the docked conformation of the most active compound 26. All the developed models were tested for robustness using various validation techniques. Furthermore, a 5-ns molecular dynamics (MD) simulation and binding free energy calculations were carried out to determine the binding modes of the inhibitors and to identify crucial interacting residues. The rationality and stability of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM/PBSA method showed the importance of the van der Waals interaction.
  
  
  
  A good correlation between the MD results, docking studies, and the contour map analysis were observed. The study has identified the key amino acid residues in Btk binding pocket. The results from this study can provide some insights into the development of potent, novel Btk inhibitors.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 61452, Republic of Korea.
authors.forename: Pavithra K
authors.initials: PK
authors.lastname: Balasubramanian
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 61452, Republic of Korea.
authors.forename: Anand
authors.initials: A
authors.lastname: Balupuri
authors.affiliation: Department of Nursing, Chosun University, Gwangju, 61452, Republic of Korea.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Kang
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 61452, Republic of Korea. chosj@chosun.ac.kr.|Department of Cellular Molecular Medicine, College of Medicine, Chosun University, Gwangju, 61452, Republic of Korea. chosj@chosun.ac.kr.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D055808:Drug Discovery; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase
keywords: Btk Kinase; COMSIA; Free energy calculation; MM/PBSA; Molecular docking; Molecular dynamic simulation