Targeting the hydrophobic pocket of autotaxin with virtual screening of inhibitors identifies a common aromatic sulfonamide structural motif

James I. Fells, Sue Lee, Derek D. Norman, Ryoko Tsukahara, Jason R. Kirby, Sandra Nelson, William Seibel, Ruben Papoian, Renukadevi Patil, Duane Miller, Abby L. Parrill, Truc Chi Pham, Daniel L. Baker, Robert Bittman, Gabor Tigyi

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Modulation of autotaxin (ATX), the lysophospholipase D enzyme that produces lysophosphatidic acid, with small-molecule inhibitors is a promising strategy for blocking the ATX-lysophosphatidic acid signaling axis. Although discovery campaigns have been successful in identifying ATX inhibitors, many of the reported inhibitors target the catalytic cleft of ATX. A recent study provided evidence for an additional inhibitory surface in the hydrophobic binding pocket of ATX, confirming prior studies that relied on enzyme kinetics and differential inhibition of substrates varying in size. Multiple hits from previous high-throughput screening for ATX inhibitors were obtained with aromatic sulfonamide derivatives interacting with the hydrophobic pocket. Here, we describe the development of a ligand-based strategy and its application in virtual screening, which yielded novel high-potency inhibitors that target the hydrophobic pocket of ATX. Characterization of the structure-activity relationship of these new inhibitors forms the foundation of a new pharmacophore model of the hydrophobic pocket of ATX.

Original languageEnglish (US)
Pages (from-to)1017-1028
Number of pages12
JournalFEBS Journal
Volume281
Issue number4
DOIs
StatePublished - Feb 1 2014

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Sulfonamides
4 alpha-glucanotransferase
Screening
Enzyme inhibition
Enzyme kinetics
Structure-Activity Relationship
Throughput
Modulation
Ligands
Derivatives
Molecules
Substrates
Enzymes
lysophosphatidic acid
alkylglycerophosphoethanolamine phosphodiesterase

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Targeting the hydrophobic pocket of autotaxin with virtual screening of inhibitors identifies a common aromatic sulfonamide structural motif. / Fells, James I.; Lee, Sue; Norman, Derek D.; Tsukahara, Ryoko; Kirby, Jason R.; Nelson, Sandra; Seibel, William; Papoian, Ruben; Patil, Renukadevi; Miller, Duane; Parrill, Abby L.; Pham, Truc Chi; Baker, Daniel L.; Bittman, Robert; Tigyi, Gabor.

In: FEBS Journal, Vol. 281, No. 4, 01.02.2014, p. 1017-1028.

Research output: Contribution to journalArticle

Fells, JI, Lee, S, Norman, DD, Tsukahara, R, Kirby, JR, Nelson, S, Seibel, W, Papoian, R, Patil, R, Miller, D, Parrill, AL, Pham, TC, Baker, DL, Bittman, R & Tigyi, G 2014, 'Targeting the hydrophobic pocket of autotaxin with virtual screening of inhibitors identifies a common aromatic sulfonamide structural motif', FEBS Journal, vol. 281, no. 4, pp. 1017-1028. https://doi.org/10.1111/febs.12674
Fells, James I. ; Lee, Sue ; Norman, Derek D. ; Tsukahara, Ryoko ; Kirby, Jason R. ; Nelson, Sandra ; Seibel, William ; Papoian, Ruben ; Patil, Renukadevi ; Miller, Duane ; Parrill, Abby L. ; Pham, Truc Chi ; Baker, Daniel L. ; Bittman, Robert ; Tigyi, Gabor. / Targeting the hydrophobic pocket of autotaxin with virtual screening of inhibitors identifies a common aromatic sulfonamide structural motif. In: FEBS Journal. 2014 ; Vol. 281, No. 4. pp. 1017-1028.
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