8Q17

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

Summary for 8Q17

• Entry DOI: 10.2210/pdb8q17/pdb
• Related: 8Q0T 8Q0U
• Descriptor: 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)
• Functional Keywords: inhibitor complex, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 65343.24

Authors

Eadsforth, T.C.,Punekar, A.S.,Green, S.R.,Baragana, B. (deposition date: 2023-07-30, release date: 2023-11-22, Last modification date: 2023-12-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.71 Å)