Abstract
Autotaxin (ATX) is considered as an interesting drug target for the therapy of several diseases. The goal of the research was to detect new ATX inhibitors which have novel scaffolds by using virtual screening. First, based on two diverse receptor-ligand complexes, 14 pharmacophore models were developed, and the 14 models were verified through a big test database. Those pharmacophore models were utilized to accomplish virtual screening. Next, for the purpose of predicting the probable binding poses of compounds and then carrying out further virtual screening, docking-based virtual screening was performed. Moreover, an excellent 3D QSAR model was established, and 3D QSAR-based virtual screening was applied for predicting the activity values of compounds which got through the above two-round screenings. A correlation coefficient r2, which equals 0.988, was supplied by the 3D QSAR model for the training set, and the correlation coefficient r2 equaling 0.808 for the test set means that the developed 3D QSAR model is an excellent model. After the filtering was done by the combinatory virtual screening, which is based on the pharmacophore modelling, docking study, and 3D QSAR modelling, we chose nine potent inhibitors with novel scaffolds finally. Furthermore, two potent compounds have been particularly discussed.
Highlights
After the filtering was done by the combinatory virtual screening, which is based on the pharmacophore modelling, docking study, and 3D QSAR modelling, we chose nine potent inhibitors with novel scaffolds
Several excluded volume spheres and chemical properties were produced and perceived as pharmacophore models; these models can be applied for discovering small molecular compounds with the capacity of inhibiting ATX activity
The genetic function approximation (GFA) model for the selectivity of a pharmacophore is built from a training set of 3285 pharmacophore models
Summary
Since the ATX-LPA signaling axis has been involved in a number of pathologies, including cancer [3,4,5,6,7], pain [8,9,10], and cholestatic pruritus [11,12], as well as fibrotic [13,14,15], inflammatory [16,17,18]. Lots of patents and literature reported numerous ATX inhibitors with probable application for the treatment of diverse pathologies [10,14,20,21,22]. Nicolas Desroy identified a first-in-class ATX inhibitor, GLPG1690, which has been undergoing clinical evaluation for the treatment of idiopathic pulmonary fibrosis [14]. The imidazo[1,2-a]pyridine series of ATX inhibitors were identified by the Nicolas Desroy and Bertrand Heckmann group [22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
