7Q52

Crystal structure of S/T protein kinase PknG from Mycobacterium tuberculosis in complex with inhibitor L2W

これはPDB形式変換不可エントリーです。

7Q52 の概要

• エントリーDOI: 10.2210/pdb7q52/pdb
• 分子名称: Serine/threonine-protein kinase PknG, FE (III) ION, 2-azanyl-3-(4-fluorophenyl)carbonyl-indolizine-1-carboxamide, ... (5 entities in total)
• 機能のキーワード: tuberculosis, inhibitor, l2w, transferase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36734.39

構造登録者

Defelipe, L.A.,Burastero, O.,Bento, I.,Garcia-Alai, M.M. (登録日: 2021-11-02, 公開日: 2022-06-22, 最終更新日: 2024-01-31)

主引用文献

Burastero, O.,Defelipe, L.A.,Gola, G.,Tateosian, N.L.,Lopez, E.D.,Martinena, C.B.,Arcon, J.P.,Traian, M.D.,Wetzler, D.E.,Bento, I.,Barril, X.,Ramirez, J.,Marti, M.A.,Garcia-Alai, M.M.,Turjanski, A.G.
Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors.
J.Med.Chem., 65:9691-9705, 2022

PubMed Abstract: Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of (). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of in infected THP-1 macrophages.

PubMed: 35737472
DOI: 10.1021/acs.jmedchem.1c02012

実験手法

X-RAY DIFFRACTION (2.35 Å)