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One‐Dimensional Inter‐ligand Nuclear Overhauser Effect – fragment based drug discovery targeting M.tuberculosis KasA
Author(s) -
Kapilashrami Kanishk,
Machutta Carl,
Picart Francis,
Bommineni Gopal Reddy,
Tonge Peter
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.681.9
Subject(s) - chemistry , ligand (biochemistry) , mycobacterium tuberculosis , stereochemistry , drug discovery , small molecule , tuberculosis , receptor , biochemistry , medicine , pathology
β‐keto‐acyl synthase A (KasA) catalyzes the decarboxylative Claisen condensation of Malonyl AcpM with the growing acyl chain in the Fatty acid biosynthesis pathway (FAS II) in Mycobacterium tuberculosis . Thiolactomycin (TLM), a natural broad spectrum antibiotic, is a competitive inhibitor of KasA, and binds to the Malonyl AcpM binding site. However, TLM has a poor K d with KasA because of lack of appropriate contacts. This study is based on the hypothesis that the pathethine chain of AcpM should be bound spatially adjacent to TLM in the active site. We use 2D NOESY‐NMR and subsequently an enhanced 1D version of the same technique to understand the relative orientation of the two ligands in the bound state. This version uses pulse field gradients and “ excitation sculpting ” to attain a higher sensitivity and cleaner, easier to interpret spectra. Understanding the relative orientation helped us design molecules with potentially higher affinity to KasA.