Development of novel therapeutics for glaucoma filtration surgery based on transforming growth factor-β receptor 1 inhibition†
Belonging to the group of cytokines, transforming growth factor-β is involved in numerous physiological processes with two of its main receptors/kinases – transforming growth factor-β receptor type 1 and 2. The inhibition of transforming growth factor-β receptor type 1 has numerous therapeutic applications, including application in glaucoma filtration surgery. This study presents QSAR modeling for a group of compounds that act as transforming growth factor-β receptor type 1 inhibitors based on field-based three dimensional modeling and the Monte Carlo method with descriptors based on the simplified molecular-input line-entry system notation and local invariants of molecular graphs. One random split of the initial data into the training and test sets was used to establish the 3D QSAR model, while for establishing conformation independent models three random splits into the training and test sets were used. The comparison of the obtained results for the molecular fragment influence on the studied activity obtained from both QSAR models revealed an excellent correlation. In order to assess the statistical quality of the developed models, different statistical approaches were applied and the results proved to be very good. The study defined molecular fragments responsible for the increase and/or decrease of the studied activity and then they were used for the computer-aided design of new compounds as potential transforming growth factor-β receptor type 1 inhibitors. The final evaluation of the established QSAR models and designed inhibitors was carried out using molecular docking studies, bringing to light an excellent correlation with the quantitative structure–activity relationship modeling results.