title: Molecular modeling studies on series of Btk inhibitors using docking, structure-based 3D-QSAR and molecular dynamics simulation: a combined approach.
abstract: Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase. It is a crucial component in BCR pathway and expressed only in hematopoietic cells except T cells and Natural killer cells. BTK is a promising target because of its involvement in signaling pathways and B cell diseases such as autoimmune disorders and lymphoma. In this work, a combined molecular modeling study of molecular docking, 3D-QSAR and molecular dynamic (MD) simulation were performed on a series of 2,5-diaminopyrimidine compounds as inhibitors targeting Btk kinase to understand the interaction and key residues involved in the inhibition. A structure based CoMFA (q (2) = 0.675, NOC = 5, r (2) = 0.961) and COMSIA (q (2) = 0.704, NOC = 6, r (2) = 0.962) models were developed from the conformation obtained by docking. The developed models were subjected to various validation techniques such as leave-five-out, external test set, bootstrapping, progressive sampling and rm (2) metrics and found to have a good predictive ability in both internal and external validation. Our docking results showed the important residues that interacts in the active site residues in inhibition of Btk kinase. Furthermore, molecular dynamics simulation was employed to study the stability of the docked conformation and to investigate the binding interactions in detail. The MD simulation analyses identified several important hydrogen bonds with Btk, including the gatekeeper residue Thr474 and Met477 at the hinge region. Hydrogen bond with active site residues Leu408 and Arg525 were also recognized. A good correlation between the MD results, docking studies and the contour map analysis are observed. This indicates that the developed models are reliable. Our results from this study can provide insights in the designing and development of more potent Btk kinase inhibitors.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 501-759, 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, 501-759, Republic of Korea.
authors.forename: Anand
authors.initials: A
authors.lastname: Balupuri
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju, 501-759, Republic of Korea. chosj@chosun.ac.kr.|Department of Cellular·Molecular Medicine, College of Medicine, Chosun University, Gwangju, 501-759, Republic of Korea. chosj@chosun.ac.kr.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase
keywords: BTK kinase; COMSIA; CoMFA; Molecular Dynamics Simulation; Molecular docking