7VJT
Crystal Structure of Mtb Pks13-TE in complex with inhibitor coumestan derivative 8
Summary for 7VJT
| Entry DOI | 10.2210/pdb7vjt/pdb |
| Descriptor | Polyketide synthase Pks13 (Termination polyketide synthase), 3,8-bis(oxidanyl)-7-(piperidin-1-ylmethyl)-[1]benzofuro[3,2-c]chromen-6-one (3 entities in total) |
| Functional Keywords | tuberculosis, mycobacterium tuberculosis, antibiotic, transferase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 2 |
| Total formula weight | 65061.03 |
| Authors | Zhang, W.,Wang, S.S.,Yu, L.F. (deposition date: 2021-09-28, release date: 2022-09-28, Last modification date: 2023-11-29) |
| Primary citation | Zhang, W.,Lun, S.,Wang, S.S.,Cai, Y.P.,Yang, F.,Tang, J.,Bishai, W.R.,Yu, L.F. Structure-Based Optimization of Coumestan Derivatives as Polyketide Synthase 13-Thioesterase(Pks13-TE) Inhibitors with Improved hERG Profiles for Mycobacterium tuberculosis Treatment. J.Med.Chem., 65:13240-13252, 2022 Cited by PubMed Abstract: Pks13 was identified as a key enzyme involved in the final step of mycolic acid biosynthesis. We previously identified antitubercular coumestans that targeted Pks13-TE, and these compounds exhibited high potency both in vitro and in vivo. However, lead compound presented potential safety concerns because it inhibits the hERG potassium channel in electrophysiology patch-clamp assays (IC = 0.52 μM). By comparing the Pks13-TE-compound complex and the ligand-binding pocket of the hERG ion channel, fluoro-substituted and oxazine-containing coumestans were designed and synthesized. Fluoro-substituted compound and oxazine-containing coumestan showed excellent antitubercular activity against both drug-susceptible and drug-resistant strains (MIC = 0.0039-0.0078 μg/mL) and exhibited limited hERG inhibition (IC ≥ 25 μM). Moreover, exhibited improved metabolic stability relative to parent compound while showing favorable bioavailability in mouse models via serum inhibition titration assays. PubMed: 36174223DOI: 10.1021/acs.jmedchem.2c01064 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.94 Å) |
Structure validation
Download full validation report
