4U3B
LpxC from A.Aaeolicus in complex with the MMP inhibitor 4-[[4-(4-chlorophenoxy)phenyl]sulfanylmethyl]tetrahydropyran-4-carbohydroxamic acid - compound 2
Summary for 4U3B
| Entry DOI | 10.2210/pdb4u3b/pdb |
| Descriptor | UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase, IMIDAZOLE, ZINC ION, ... (6 entities in total) |
| Functional Keywords | antibacterial, lpxc, gram negative bacteria, mmp, hydrophobe, hydrolase |
| Biological source | Aquifex aeolicus |
| Total number of polymer chains | 1 |
| Total formula weight | 31654.20 |
| Authors | Olivier, N.B. (deposition date: 2014-07-19, release date: 2014-10-01, Last modification date: 2024-05-08) |
| Primary citation | Murphy-Benenato, K.E.,Olivier, N.,Choy, A.,Ross, P.L.,Miller, M.D.,Thresher, J.,Gao, N.,Hale, M.R. Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors. Acs Med.Chem.Lett., 5:1213-1218, 2014 Cited by PubMed Abstract: In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization. PubMed: 25408833DOI: 10.1021/ml500210x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.34 Å) |
Structure validation
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