6hk4

Crystal structure of GSK-3B in complex with pyrazine inhibitor C22

spinqualitylabelsall models 6hk4, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hk4 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: DMS, G8E, GOL, MLI, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed It is widely accepted that drug-target association and dissociation rates directly affect drug efficacy and safety. To rationally optimize drug binding kinetics, one must know the atomic arrangement of the protein-ligand complex during the binding/unbinding process in order to detect stable and metastable states. Whereas experimental approaches can determine kinetic constants with fairly good accuracy, computational approaches based on molecular dynamics (MD) simulations can deliver the atomistic details of the unbinding process. Furthermore, they can also be utilized prospectively to predict residence time (i.e., the inverse of unbinding kinetics constant, koff) with an acceptable level of accuracy. Here, we report a novel method based on adiabatic bias MD with an electrostatics-like collective variable (dubbed elABMD) for sampling protein-ligand dissociation events in two kinases. elABMD correctly ranked a ligand series on glucokinase, in agreement with experimental data and previous calculations. Subsequently, we applied the new method prospectively to a congeneric series of GSK-3beta inhibitors. For this series, new crystal structures were generated and the residence time was experimentally measured with surface plasmon resonance (SPR). There was good agreement between computational predictions and experimental measures, suggesting that elABMD is an innovative and efficient tool for calculating residence times. Investigating Drug-Target Residence Time in Kinases through Enhanced Sampling Simulations.,Gobbo D, Piretti V, Di Martino RMC, Tripathi SK, Giabbai B, Storici P, Demitri N, Girotto S, Decherchi S, Cavalli A J Chem Theory Comput. 2019 Jul 12. doi: 10.1021/acs.jctc.9b00104. PMID:31246463 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glycogen synthase kinase 3 3D structures

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