title: Targeting the hydrophobic pocket of autotaxin with virtual screening of inhibitors identifies a common aromatic sulfonamide structural motif.
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.
authors: Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors: James I
authors: JI
authors: Fells
authors: Sue Chin
authors: SC
authors: Lee
authors: Derek D
authors: DD
authors: Norman
authors: Ryoko
authors: R
authors: Tsukahara
authors: Jason R
authors: JR
authors: Kirby
authors: Sandra
authors: S
authors: Nelson
authors: William
authors: W
authors: Seibel
authors: Ruben
authors: R
authors: Papoian
authors: Renukadevi
authors: R
authors: Patil
authors: Duane D
authors: DD
authors: Miller
authors: Abby L
authors: AL
authors: Parrill
authors: Truc-Chi
authors: TC
authors: Pham
authors: Daniel L
authors: DL
authors: Baker
authors: Robert
authors: R
authors: Bittman
authors: Gabor
authors: G
authors: Tigyi
mesh_terms: D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D000099189:Lysophospholipase D
chemical_list: D010727:Phosphoric Diester Hydrolases; D013449:Sulfonamides; D000099189:Lysophospholipase D
keywords: autotaxin; enzymology; inhibitors; virtual screening