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    • Docking studies were performed on the

    2023-01-30

    Docking studies were performed on the selected compounds to explore their binding patterns and to examine SAR in more detail. The co-crystal structure of ATX in complex with PF-8380 (PDB code: ) was selected for the docking studies due to structural similarity of the most potent compound with PF-8380. The chemical structure of PF-8380 is provided in Fig. S1. The co-crystallized ligand (PF-8380) was extracted from the crystal structure and re-docked in the active site of ATX to validate the docking protocol. Docking procedure is generally considered rational if the root mean square deviation (RMSD) value between the crystal and re-docked structures is lower than 2Å. Comparison between crystal and re-docked conformations of the ligand is shown in Fig. S2. As can be seen in the figure, both conformations displayed same binding mode as well as identical binding interactions. Furthermore, a RMSD value of 0.479Å between both conformations suggested that docking procedure was reliable for searching the binding patterns of other compounds. Binding mode and binding interactions of compound are displayed in (A–C). In the A, proposed binding mode of is compared with PF-8380. It can be seen that compound was well aligned with PF-8380 inside the active site of ATX. This suggests that binding mode of newly synthesized compounds is similar as that of PF-8380. In the docked structure, lipophilic dichloro-phenyl group of compound was placed within the hydrophobic pocket enclosed with Ile167, Leu213, Leu216, Ala217, Trp260, Phe273 and Phe274 residues (C). The carbamate carbonyl served as a hydrogen bond acceptor to Trp275 NH group. Compound extended through the hydrophilic core and the methylphosphonic Carmustine group at R position showed electrostatic interaction with catalytic zinc ion. In addition, R group formed hydrogen bonds with Asn230 and active site water molecules (B). Presumably, these interactions are responsible for the higher potency of compound as compared to other compounds of the series. It can be seen in (A–C) that replacement of methylphosphonic acid group () at R position with methanesulfonamide (), chloro () and methoxy () substituents lead to the loss of head group interactions and thus they display lower activities than . Compound possess sulfonamide group at R which showed hydrogen bonding interactions with active site water molecule as well as electrostatic interaction with catalytic zinc ion (A). This could be reason for higher activity of than which lacks R substitution (B). Compound possesses much lower activity than because of the absence of the R substitution which plays an important role in the binding. In addition, methanesulfonamide group at R position failed to produce interactions with catalytic zinc ion and active site water molecules (B). Docking results showed that lack of carbonyl group at R position in compounds and limited the extension of these molecule in the active site. As a result, methylphosphonic acid group at their R position formed hydrogen bond with Thr209 instead of Asn230 (A and B). In case of , benzene ring of the R substitution was slightly deflected due to the presence of pyrrolidine ring rather than piperidine ring (). Consequently, R substitution of exhibited more hydrophobic interactions than (A and B). This could be the reason for higher activity of than . Compound showed the similar binding interactions as (C) but due to the omission of dichloro groups at R position, hydrophobic interactions with Ile167, Leu216 and Trp260 were lost (C). This could be responsible for the lower activity of than . On the basis of our model, a conclusion was drawn that the 4-formylamino-piperidine-1-carboxylic acid 3,5-dichloro-benzyl ester moiety at R position and methylphosphonic acid group at R position are important for the inhibition of ATX. Two highly potent compounds and were selected for the human plasma assay. As shown in , compound demonstrated far better activity (IC=14.99nM) than compound (IC=735.00nM). Moreover, compound displayed higher potency than the clinical compound, GLPG1690 (IC=242.00nM) in the human plasma assay. Consequently, compound could serve as a promising lead compound for further biological evaluation and optimization.