Molecular modelling guided design, synthesis and QSAR analysis of new small molecule non-lipid autotaxin inhibitors

Abstract The lysophospholipase D autotaxin (ATX) generates lysophosphatidic acid (LPA) that activates six cognate G-protein coupled receptors (GPCR) in cancerous cells, promoting their motility and invasion. Four novel compounds were generated aided by molecular docking guided design and synthesis techniques to obtain new dual inhibitors of ATX and the lysophosphatidic acid receptor subtype 1 (LPAR1). Biological evaluation of these compounds revealed two compounds, 10 and 11, as new ATX enzyme inhibitors with potencies in the range of 218–220 nM and water solubility (>100 µg/mL), but with no LPAR1 inhibitory activity. A QSAR model was generated that included four newly designed compounds and twenty-one additional compounds that we have reported previously. The QSAR model provided excellent predictability of the pharmacological activity and potency among structurally related drug candidates. This model will be highly useful in guiding the synthesis of new ATX inhibitors in the future.