title: Thiolactomycin-based β-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.
abstract: Thiolactomycin (TLM) is a natural product inhibitor of KasA, the β-ketoacyl synthase A from Mycobacterium tuberculosis. To improve the affinity of TLM for KasA, a series of TLM analogs have been synthesized based on interligand NOEs between TLM and a pantetheine analog when both are bound simultaneously to the enzyme. Kinetic binding data reveal that position 3 of the thiolactone ring is a suitable position for elaboration of the TLM scaffold, and the structure-activity relationship studies provide information on the molecular features that govern time-dependent inhibition in this enzyme system. These experiments also exemplify the utility of transient one-dimensional NOE spectroscopy for obtaining interligand NOEs compared with traditional steady state two-dimensional NOESY spectroscopy.
authors.affiliation: Department of Chemistry, Institute for Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Kanishk
authors.initials: K
authors.lastname: Kapilashrami
authors.forename: Gopal R
authors.initials: GR
authors.lastname: Bommineni
authors.forename: Carl A
authors.initials: CA
authors.lastname: Machutta
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.forename: Cheng-Tsung
authors.initials: CT
authors.lastname: Lai
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
authors.forename: Francis
authors.initials: F
authors.lastname: Picart
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D020102:Mycobacterium smegmatis / Q000201:enzymology / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000201:enzymology* / Q000235:genetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013876:Thiophenes; C035068:thiolactomycin; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase