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Open AccessArticle

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

1
Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece
2
NovaMechanics Ltd, Princess De Tyras 16, 1065 Nicosia, Cyprus
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7002; https://doi.org/10.3390/ijms21197002
Received: 1 September 2020 / Revised: 18 September 2020 / Accepted: 19 September 2020 / Published: 23 September 2020
(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2020)
Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design. View Full-Text
Keywords: atotaxin; small molecules; ATX inhibitors; in silico screening atotaxin; small molecules; ATX inhibitors; in silico screening
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Magkrioti, C.; Kaffe, E.; Stylianaki, E.-A.; Sidahmet, C.; Melagraki, G.; Afantitis, A.; Matralis, A.N.; Aidinis, V. Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors. Int. J. Mol. Sci. 2020, 21, 7002.

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