6B2Q

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

Summary for 6B2Q

• Entry DOI: 10.2210/pdb6b2q/pdb
• Descriptor: Serine/threonine-protein kinase PknA, 5-{5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}thiophene-2-sulfonamide, 3-methyl-1-(2-methylpropyl)butyl 4-O-beta-L-gulopyranosyl-beta-D-glucopyranoside (3 entities in total)
• Functional Keywords: kinase, drug design, tuberculosis, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cell membrane ; Single-pass membrane protein : A5TY85
• Total number of polymer chains: 4
• Total formula weight: 138123.40

Authors

Zuccola, H.J. (deposition date: 2017-09-20, release date: 2018-02-14, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.88 Å)