SAR study on Novel truxillic acid monoester-Based inhibitors of fatty acid binding proteins as Next-Generation antinociceptive agents

Recent Advances on Small-Molecule Inhibitors of Lipocalin-like Proteins

“…These contributed to the selectivity for FABP3 over FABP5 and FABP7. 124 Hyder et al also screened FABP3 inhibitors from plants with antidiabetic effects through molecular docking analysis using the Molecular Operating Environment and identified >10 naturally occurring carboxylic acids that could serve as potential candidates for FABP3 inhibitors. 125 Although the inhibitors targeting FABP3 may have potential applications in clinical situations such as Parkinson's disease, nociception, ischemic stroke, and diabetes, the FABP3knockout mice showed age-related cardiac hypertrophy.…”

“…The selectivity over FABP3 could be explained by the presence of the 2-indanyl ester that causes van der Waals clashes with Thr29, Phe57, and Lys58 in FABP3, whereas these clashes were not present in the binding with FABP5. 124 Apart from the TAMEs, these researchers also screened a series of inhibitors with a new scaffold that was also based on SB-FI-26. Molecular docking was used to screen approximately two million compounds from the ZINC database with the Xray crystallography data of how SB-FI-26 binds FABP5 as reference.…”

“…For FABP7, although the size of the binding pocket is between FABP3 and FABP5, no hydrogen bonds formed due to the binding pose of compound 102 in FABP7. These contributed to the selectivity for FABP3 over FABP5 and FABP7 . Hyder et al also screened FABP3 inhibitors from plants with antidiabetic effects through molecular docking analysis using the Molecular Operating Environment and identified >10 naturally occurring carboxylic acids that could serve as potential candidates for FABP3 inhibitors …”

“…The typical interaction of the carboxyl group of the inhibitor with Arg129 and Tyr131 and the hydrophobic interaction between the ester of the inhibitor and the S3–S4 loop and neighboring α-helixes of the lipocalin domain contributed to the high affinity. The selectivity over FABP3 could be explained by the presence of the 2-indanyl ester that causes van der Waals clashes with Thr29, Phe57, and Lys58 in FABP3, whereas these clashes were not present in the binding with FABP5 …”

“…The SB-FI-26 derivatives, SB-FI-50, SB-FI-60, and SB-FI-62, also showed good binding affinities with K i values of 0.6, 0.3, and 6.1 μM, respectively . Other TAMEs were screened using the SAR approach, and compound 113 served as the most selective FABP7 inhibitor (FABP7/3 SI = 81.8) with an excellent affinity ( K i = 0.83 μM). , Compound 113 could accommodate the canonical binding site with 3-(3,6-dihydro-2 H -pyran-4-yl)­phenyl ester forming additional hydrogen bonds with Arg79 and Gln96. The selectivity over FABP3 is achieved by the phenyl ester moiety.…”