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

• Published in: The FEBS journal Vol. 281; no. 4; pp. 1017 - 1028
• Main Authors: Fells, James I., Lee, Sue Chin, Norman, Derek D., Tsukahara, Ryoko, Kirby, Jason R., Nelson, Sandra, Seibel, William, Papoian, Ruben, Patil, Renukadevi, Miller, Duane D., Parrill, Abby L., Pham, Truc‐Chi, Baker, Daniel L., Bittman, Robert, Tigyi, Gabor
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-02-2014
• Subjects: autotaxin; Biocatalysts; Enzyme kinetics; enzymology; Hydrophobic and Hydrophilic Interactions; Inhibitor drugs; inhibitors; Molecular Structure; Pharmacology; Phosphoric Diester Hydrolases - chemistry; Structure-Activity Relationship; Studies; Sulfonamides - chemistry; virtual screening; inhibitors; virtual screening; autotaxin; enzymology
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.12674

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.
A ligand‐based virtual screening method identified a series of novel autotaxin inhibitors containing an aromatic sulfonamide motif. Biochemical testing revealed that the majority of the compounds inhibited the cleavage of the lysophospholipase substrate FS‐3, while enhancing the cleavage of the phosphodiesterase substrate pNP‐TMP. Docking simulation demonstrated that this class of compounds binds to the hydrophobic pocket of autotaxin, thereby selectively blocking LPC‐like substrates but allowing pNP‐TMP to still bind.