Revisiting Bruton’s Tyrosine Kinase Inhibitor Landscape with Computational Microscope
Mentor 1
Arjun Saha
Start Date
28-4-2023 12:00 AM
Description
Bruton's Tyrosine Kinase (BTK) is an enzyme that plays an important role in the signaling pathways of some immune cells and particularly B cells . Mutations in the BTK gene may cause a genetic disorder called X-linked gammaglobulinemia (XLA) which impacts the ability of the immune system to make antibodies, leading to a high susceptibility to bacterial infections and autoimmune disorders. Several BTK inhibitors have been approved by the FDA for treatment of B-cell related malignancies and inflammatory diseases, and other promising inhibitors are being evaluated. Covalent inhibitors bind to the cystine 481 residue of BTK. The purpose of my research is to use molecular docking simulation tools and molecular dynamics simulations to examine and compare the conformations and binding energies of 9 BTK inhibitors available as crystal structures. The protein will be relaxed using molecular dynamics simulation and then docked with the inhibitors using three docking software packages. Molecular dynamics will be performed using GROMACS, an open-source software tool. Docking will be performed using three software packages, e.g., AutoDock, AutoDock Vina, and AutoDockFR. Covalent and non-covalent docking will be examined. The results will be compared to the conformations of the experimentally reported crystal structures of the inhibitors to evaluate the accuracy and precision of these software packages.
Revisiting Bruton’s Tyrosine Kinase Inhibitor Landscape with Computational Microscope
Bruton's Tyrosine Kinase (BTK) is an enzyme that plays an important role in the signaling pathways of some immune cells and particularly B cells . Mutations in the BTK gene may cause a genetic disorder called X-linked gammaglobulinemia (XLA) which impacts the ability of the immune system to make antibodies, leading to a high susceptibility to bacterial infections and autoimmune disorders. Several BTK inhibitors have been approved by the FDA for treatment of B-cell related malignancies and inflammatory diseases, and other promising inhibitors are being evaluated. Covalent inhibitors bind to the cystine 481 residue of BTK. The purpose of my research is to use molecular docking simulation tools and molecular dynamics simulations to examine and compare the conformations and binding energies of 9 BTK inhibitors available as crystal structures. The protein will be relaxed using molecular dynamics simulation and then docked with the inhibitors using three docking software packages. Molecular dynamics will be performed using GROMACS, an open-source software tool. Docking will be performed using three software packages, e.g., AutoDock, AutoDock Vina, and AutoDockFR. Covalent and non-covalent docking will be examined. The results will be compared to the conformations of the experimentally reported crystal structures of the inhibitors to evaluate the accuracy and precision of these software packages.
