6B2P

Dual Inhibition of the Essential Protein Kinases A and B in Mycobacterium tuberculosis

6B2P の概要

• エントリーDOI: 10.2210/pdb6b2p/pdb
• 分子名称: Serine/threonine-protein kinase PknB, 5-{5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}thiophene-2-sulfonamide (2 entities in total)
• 機能のキーワード: kinase, drug design, tuberculosis, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cell membrane ; Single-pass membrane protein : P9WI80
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30684.03

構造登録者

Zuccola, H.J. (登録日: 2017-09-20, 公開日: 2018-02-14, 最終更新日: 2024-03-13)

主引用文献

Wang, T.,Bemis, G.,Hanzelka, B.,Zuccola, H.,Wynn, M.,Moody, C.S.,Green, J.,Locher, C.,Liu, A.,Gao, H.,Xu, Y.,Wang, S.,Wang, J.,Bennani, Y.L.,Thomson, J.A.,Muh, U.
Mtb PKNA/PKNB Dual Inhibition Provides Selectivity Advantages for Inhibitor Design To Minimize Host Kinase Interactions.
ACS Med Chem Lett, 8:1224-1229, 2017

PubMed Abstract: Drug resistant tuberculosis (TB) infections are on the rise and antibiotics that inhibit through a novel mechanism could be an important component of evolving TB therapy. Protein kinase A (PknA) and protein kinase B (PknB) are both essential serine-threonine kinases in . Given the extensive knowledge base in kinase inhibition, these enzymes present an interesting opportunity for antimycobacterial drug discovery. This study focused on targeting both PknA and PknB while improving the selectivity window over related mammalian kinases. Compounds achieved potent inhibition ( ≈ 5 nM) of both PknA and PknB. A binding pocket unique to mycobacterial kinases was identified. Substitutions that filled this pocket resulted in a 100-fold differential against a broad selection of mammalian kinases. Reducing lipophilicity improved antimycobacterial activity with the most potent compounds achieving minimum inhibitory concentrations ranging from 3 to 5 μM (1-2 μg/mL) against the H37Ra isolate of .

PubMed: 29259738
DOI: 10.1021/acsmedchemlett.7b00239

実験手法

X-RAY DIFFRACTION (3.01 Å)