8Q17

Identification and optimisation of novel inhibitors of the Polyketide synthetase 13 thioesterase domain with antitubercular activity

8Q17 の概要

• エントリーDOI: 10.2210/pdb8q17/pdb
• 関連するPDBエントリー: 8Q0T 8Q0U
• 分子名称: Polyketide synthase Pks13, SULFATE ION, ~{N}-[2-[4-(azetidin-1-ylcarbonyl)phenyl]ethyl]-3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazole-5-carboxamide, ... (6 entities in total)
• 機能のキーワード: inhibitor complex, 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: 65343.24

構造登録者

Eadsforth, T.C.,Punekar, A.S.,Green, S.R.,Baragana, B. (登録日: 2023-07-30, 公開日: 2023-11-22, 最終更新日: 2023-12-06)

主引用文献

Green, S.R.,Wilson, C.,Eadsforth, T.C.,Punekar, A.S.,Tamaki, F.K.,Wood, G.,Caldwell, N.,Forte, B.,Norcross, N.R.,Kiczun, M.,Post, J.M.,Lopez-Roman, E.M.,Engelhart, C.A.,Lukac, I.,Zuccotto, F.,Epemolu, O.,Boshoff, H.I.M.,Schnappinger, D.,Walpole, C.,Gilbert, I.H.,Read, K.D.,Wyatt, P.G.,Baragana, B.
Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity.
J.Med.Chem., 66:15380-15408, 2023

PubMed Abstract: There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and ADMET profiles.

PubMed: 37948640
DOI: 10.1021/acs.jmedchem.3c01514

実験手法

X-RAY DIFFRACTION (1.71 Å)