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    • In conclusion we have designed and synthesized a series of

    2023-08-01

    In conclusion, we have designed and synthesized a series of 4-phenyl-thiazole analogues as potent ATX inhibitors. Total twenty-five compounds were synthesized and evaluated for their inhibitory activity on ATX using FS-3 and human plasma assays. Compound was found to be the most potent derivative prepared in this series. Binding mode and binding interactions of this series of compounds were predicted through docking studies. Docking results identified the key amino nadph oxidase inhibitor residues in the active site of ATX which play an important role in the inhibition. Docking results also suggested that Asn230 and Trp275 participate in hydrogen bonding while Ile167, Leu213, Leu216, Ala217, Leu243, Trp260, Phe273, Phe274 and Tyr306 are involved in the hydrophobic interactions. Additionally, electrostatic interaction with catalytic zinc ion and hydrogen bonds with active site water molecules are crucial to inhibit ATX. This combined , and study offers a comprehensive insight into the SAR and binding mode of these small molecule ATX inhibitors, which could further aid the design of novel ATX inhibitors. Overall, this work provides a promising ATX inhibitor () for the further evaluation and development. This compound demonstrated higher potency than PF-8380 in the FS-3 assay and also exhibited far better inhibitory activity than clinical ATX inhibitor (GLPG1690) in the human plasma assay. Conflict of interest
    Acknowledgments This study was financially supported by research fund of Chungnam National University.
    Introduction Autotaxin (ATX, NPP2, lysoPLD) is a ubiquitous, secreted enzyme in the nucleotide pyrophosphatase/phosphodiesterase (NPP) family.1, 2, 3, 4 NPP1–4 are capable of hydrolyzing phosphoanhydrides whereas NPP 2, 6, and 7 hydrolyze phosphodiester linkages.1, 5, 6 To date the natural substrate for NPP5 remains unknown. Within this family only ATX is capable of cleaving both phosphoanhydride and phosphate ester bonds, although it exhibits preference for phosphate esters.2, 3, 7, 8 Regiochemically, ATX has lysophospholipase-D (lysoPLD) activity, allowing it to hydrolyze lysophosphatidylcholine (LPC) to generate the bioactive lipid, lysophosphatidic acid (LPA) and choline (Scheme 1).1, 2, 3 Through this lysoPLD activity, ATX is the primary source of plasma LPA. Much of the biological activity of ATX can be attributed to LPA, which prompts several signaling cascades through the activation of specific G-protein coupled receptors which stimulate cell proliferation, survival and migration.10, 11, 12 Through this downstream signaling of LPA, ATX is necessary for embryonic development of the neural tube and also plays a role in wound healing.13, 14, 15 ATX also plays an essential role in blood vessel formation during embryogenesis as knockouts are non-viable due to defects in angiogenesis. However, upregulated ATX and subsequently increased level of LPA have been linked to oncogenic transformation, cancer metastasis and therapeutic resistance, cardiovascular disease, Alzheimer’s disease, and neuropathic pain.3, 11, 17, 18, 19 The relationship between ATX and human disease makes it a potential therapeutic target. The goal of this project is to discover novel small-molecule non-lipid drug-like inhibitors of ATX by use of a structure-based pharmacophore, targeting the hydrophobic tunnel of ATX. Pharmacophores are geometrical models of structural features important for biological activity. Pharmacophores can be either ligand-based, where ligand commonalities alone are utilized, or structure-based, where ligand similarities are taken into account in context of their interactions in a target protein. North et al., Mize et al., and Norman et al. utilized ligand-based techniques to develop pharmacophores for ATX, but the present work differs because it is one of the first structure-based pharmacophores for ATX (Fells et al. also reported a structure-based pharmacophore targeting the hydrophobic pocket of ATX).22, 23, 24, 25 Recent crystallized structures of ATX are useful tools from which to develop structure-based pharmacophores.26, 27, 28, 29, 30 Crystal structures of mouse, rat, and human ATX all are composed of three main domains, including a catalytic domain, which contains a polar active site, a hydrophobic tunnel, and a hydrophobic pocket (Fig. 1). The prevalence of non-polar amino acid sidechains in the hydrophobic tunnel of ATX might lead to a structure-based pharmacophore that contains predominantly non-specific hydrophobic features, capable of finding compounds which fit into the ATX hydrophobic pocket but may also bind to other receptors. Aromatic features can provide essential interaction directionality that can potentially improve specificity as aromatic rings show strong preference to interact in either an edge-to-face or face-to-face orientation. Aromatic features were deliberately included in the pharmacophore utilized here in high-throughput virtual screening of large databases to discover a variety of new and hopefully selective scaffolds for potential inhibitors which may be worthwhile to pursue further with structure–activity relationship studies.