7VJT

Crystal Structure of Mtb Pks13-TE in complex with inhibitor coumestan derivative 8

7VJT の概要

• エントリーDOI: 10.2210/pdb7vjt/pdb
• 分子名称: Polyketide synthase Pks13 (Termination polyketide synthase), 3,8-bis(oxidanyl)-7-(piperidin-1-ylmethyl)-[1]benzofuro[3,2-c]chromen-6-one (3 entities in total)
• 機能のキーワード: tuberculosis, mycobacterium tuberculosis, antibiotic, transferase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65061.03

構造登録者

Zhang, W.,Wang, S.S.,Yu, L.F. (登録日: 2021-09-28, 公開日: 2022-09-28, 最終更新日: 2023-11-29)

主引用文献

Zhang, W.,Lun, S.,Wang, S.S.,Cai, Y.P.,Yang, F.,Tang, J.,Bishai, W.R.,Yu, L.F.
Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis Treatment.
J.Med.Chem., 65:13240-13252, 2022

PubMed Abstract: Pks13 was identified as a key enzyme involved in the final step of mycolic acid biosynthesis. We previously identified antitubercular coumestans that targeted Pks13-TE, and these compounds exhibited high potency both in vitro and in vivo. However, lead compound presented potential safety concerns because it inhibits the hERG potassium channel in electrophysiology patch-clamp assays (IC = 0.52 μM). By comparing the Pks13-TE-compound complex and the ligand-binding pocket of the hERG ion channel, fluoro-substituted and oxazine-containing coumestans were designed and synthesized. Fluoro-substituted compound and oxazine-containing coumestan showed excellent antitubercular activity against both drug-susceptible and drug-resistant strains (MIC = 0.0039-0.0078 μg/mL) and exhibited limited hERG inhibition (IC ≥ 25 μM). Moreover, exhibited improved metabolic stability relative to parent compound while showing favorable bioavailability in mouse models via serum inhibition titration assays.

PubMed: 36174223
DOI: 10.1021/acs.jmedchem.2c01064

実験手法

X-RAY DIFFRACTION (1.94 Å)