6HK7

Crystal structure of GSK-3B in complex with pyrazine inhibitor C50

6HK7 の概要

• エントリーDOI: 10.2210/pdb6hk7/pdb
• 分子名称: Glycogen synthase kinase-3 beta, GLYCEROL, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: gsk 3b, complex, pyrazine, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40130.08

構造登録者

Piretti, V.,Giabbai, B.,Demitri, N.,Di Martino, R.,Tripathi, S.K.,Gobbo, D.,Decherchi, S.,Storici, P.,Girotto, S.,Cavalli, A. (登録日: 2018-09-05, 公開日: 2019-07-17, 最終更新日: 2024-11-13)

主引用文献

Gobbo, D.,Piretti, V.,Di Martino, R.M.C.,Tripathi, S.K.,Giabbai, B.,Storici, P.,Demitri, N.,Girotto, S.,Decherchi, S.,Cavalli, A.
Investigating Drug-Target Residence Time in Kinases through Enhanced Sampling Simulations.
J Chem Theory Comput, 15:4646-4659, 2019

PubMed Abstract: 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, ) 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-3β 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.

PubMed: 31246463
DOI: 10.1021/acs.jctc.9b00104

実験手法

X-RAY DIFFRACTION (3.2 Å)