Thiolactomycin-based beta-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.

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Kapilashrami K, Bommineni GR, Machutta CA, Kim P, Lai CT, Simmerling C, Picart F, Tonge PJ

Thiolactomycin-based beta-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.

J Biol Chem. 2013 Mar 1;288(9):6045-52. doi: 10.1074/jbc.M112.414516. Epub 2013 Jan 10.

PubMed ID

23306195 [ View in PubMed

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Abstract

Thiolactomycin (TLM) is a natural product inhibitor of KasA, the beta-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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-Hydroxy-3,5-Dimethyl-5-(2-Methyl-Buta-1,3-Dienyl)-5h-Thiophen-2-One	3-oxoacyl-[acyl-carrier-protein] synthase 1	Kd (nM)	2.26E+05	8.5	N/A	Details