8q0u | pdb_00008q0u
Identification and optimisation of novel inhibitors of the Polyketide synthetase 13 thioesterase domain with antitubercular activity
Structural highlights
FunctionPKS13_MYCTU Involved in the biosynthesis of mycolic acids (PubMed:19436070, PubMed:23770708, PubMed:25467124). Forms, with FadD32, the initiation module of the mycolic condensation system (PubMed:19436070, PubMed:19477415, PubMed:25467124). Synthesizes, in coupled reaction with FadD32, the biosynthetic precursors of mycolic acids, alpha-alkyl beta-ketoacids, via the condensation of two long chain fatty acid derivatives, a very long meromycoloyl-AMP and a shorter 2-carboxyacyl-CoA (PubMed:19436070, PubMed:25467124). The acyl chain of the acyl-AMP produced by FadD32 is specifically transferred onto the N-terminal ACP domain of Pks13, and then transferred onto the KS domain. The extender unit carboxyacyl-CoA is specifically loaded onto the AT domain, which catalyzes the covalent attachment of the carboxyacyl chain to its active site, and its subsequent transfer onto the P-pant arm of the C-terminal ACP domain. The KS domain catalyzes the condensation between the two loaded fatty acyl chains to produce an alpha-alkyl beta-ketothioester linked to the C-ACP domain (PubMed:19436070). Then, the thioesterase-like domain acts as a transacylase and is responsible for both the release and the transfer of the alpha-alkyl beta-ketoacyl chain onto a polyol acceptor molecule, particularly trehalose, leading to the formation of the trehalose monomycolate precursor (PubMed:25467124).[1] [2] [3] [4] Publication Abstract from PubMedThere 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 Mycobacterium tuberculosis 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 muM) and in vitro ADMET profiles. Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity.,Green SR, Wilson C, Eadsforth TC, Punekar AS, Tamaki FK, Wood G, Caldwell N, Forte B, Norcross NR, Kiczun M, Post JM, Lopez-Roman EM, Engelhart CA, Lukac I, Zuccotto F, Epemolu O, Boshoff HIM, Schnappinger D, Walpole C, Gilbert IH, Read KD, Wyatt PG, Baragana B J Med Chem. 2023 Nov 10. doi: 10.1021/acs.jmedchem.3c01514. PMID:37948640[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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