A multifaceted approach to identify non-specific enzyme inhibition: Application to Mycobacterium tuberculosis shikimate kinase

Mansour S. Alturki, Ngolui Rene Fuanta, Madison A. Jarrard, Judith V. Hobrath, Douglas C. Goodwin, Thankhoe A. Rants'o, Angela I. Calderón (Lead / Corresponding author)

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4 Citations (Scopus)
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Abstract

Single dose high-throughput screening (HTS) followed by dose-response evaluations is a common strategy for the identification of initial hits for further development. Early identification and exclusion of false positives is a cost-saving and essential step in early drug discovery. One of the mechanisms of false positive compounds is the formation of aggregates in assays. This study evaluates the mechanism(s) of inhibition of a set of 14 compounds identified previously as actives in Mycobacterium tuberculosis (Mt) cell culture screening and in vitro actives in Mt shikimate kinase (MtSK) assay. Aggregation of hit compounds was characterized using multiple experimental methods, LC-MS, 1HNMR, dynamic light scattering (DLS), transmission electron microscopy (TEM), and visual inspection after centrifugation for orthogonal confirmation. Our results suggest that the investigated compounds containing oxadiazole-amide and aminobenzothiazole moieties are false positive hits and non-specific inhibitors of MtSK through aggregate formation.

Original languageEnglish
Pages (from-to)802-808
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number4
Early online date5 Dec 2017
DOIs
Publication statusPublished - 15 Feb 2018

Keywords

  • Aggregator
  • LC-MS
  • MtSK
  • NMR
  • Non-specific inhibition
  • Triton X-100

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    Alturki, M. S., Fuanta, N. R., Jarrard, M. A., Hobrath, J. V., Goodwin, D. C., Rants'o, T. A., & Calderón, A. I. (2018). A multifaceted approach to identify non-specific enzyme inhibition: Application to Mycobacterium tuberculosis shikimate kinase. Bioorganic and Medicinal Chemistry Letters, 28(4), 802-808. https://doi.org/10.1016/j.bmcl.2017.12.002