Identification of two novel chemical classes of Autotaxin (ATX) inhibitors using enalos asclepios KNIME nodes

In this study, we present an effort of identifying ATX inhibitors that bind to allosteric ATX binding sites using the Enalos Asclepios KNIME Node. All the available PDB crystal structures of ATX were collected, prepared, and aligned. Visual examination of these structures led to the identification of four crystal structures of human ATX co-crystallized with four known inhibitors. These inhibitors bind to five binding sites with five different binding modes. These five binding sites were thereafter used to virtually screen a compound library of 14,000 compounds to identify molecules that bind to allosteric sites. Based on the binding mode and interactions, the docking score, and the frequency that a compound comes up as a top-ranked among the five binding sites, 24 compounds were selected for in vitro testing. Finally, two compounds emerged with inhibitory activity against ATX in the low micromolar range, while their mode of inhibition and binding pattern were also studied. The two derivatives identified herein can serve as "hits" towards developing novel classes of ATX allosteric inhibitors.PMID:38447786 | DOI:10.1016/j.bmcl.2024.129690

Source: Bioorganic and Medicinal Chemistry Letters - March 6, 2024 Category: Chemistry Authors: Elli-Anna Stylianaki Varnavas D Mouchlis Christiana Magkrioti Konstantinos D Papavasileiou Antreas Afantitis Alexios N Matralis Vassilis Aidinis Source Type: research