Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

• Main Authors: Christiana Magkrioti, Eleanna Kaffe, Elli-Anna Stylianaki, Camelia Sidahmet, Georgia Melagraki, Antreas Afantitis, Alexios N. Matralis, Vassilis Aidinis
• Format: Article
• Language: English
• Published: MDPI AG 2020-09-01
• Series: International Journal of Molecular Sciences
• Subjects: atotaxin; small molecules; ATX inhibitors; in silico screening
• Online Access: https://www.mdpi.com/1422-0067/21/19/7002
• ISSN: 1661-6596; 1422-0067

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.