Figure 8
Structural similarity of the GSK-J4 and the TβRI inhibitor GW85585741 suggests that GSK-J4 off-targeting TβRI predicted by FINDSITEcomb2.0 is plausible. Their respective chemical structures are shown in (a) GSK-J4 and (b) GW855857. When GSK-J4 in the ester form is turned into the active acid form GSK-J1, the latter inhibits H3K27 histone demethylase52. GW855857 inhibits TβRI (ALK5)41. Using the PyMOL Molecular Graphics System Version 2.3.2 (Schrödinger, LLC), the GSK-J1 ligand structure (from PDB: 4ASK)52 was manually docked into the GW855857 binding pocket in its inhibitory complex crystal structure with TβRI (PDB: 3HMM)41. (c) Pose 1 of GSK-J4 (thin sticks, carbon in green) is generated based on spatially matching its common scaffold with GW855857 (thick sticks, carbon in white). Pose 1 allows for potential polar interactions between the carboxylic group of the docked GSK-J4 and the TβRI residues near the solvent exposed pocket entrance. (d) Pose 2 is rotated approximately 120 oC within the ligand plane from Pose 1 and appears to allow for a better steric fit in the pocket.
