IN SILICO SCREENING FOR SAFER FFAR1 ALLOSTERIC MODULATORS: INTEGRATION OF PHARMACOPHORE MODELING, MOLECULAR DOCKING, ADMET PROFILING, AND MOLECULAR DYNAMICS

The FFAR1 receptor (GPR40), predominantly expressed in pancreatic β-cells, plays a key role in insulin secretion. The allosteric agonist TAK-875 was discontinued due to hepatotoxicity, but its pharmacophore remains valuable for developing novel selective modulators. This study aimed to identify new FFAR1 ligands with suitable affinity and a more favorable toxicological profile than TAK-875. Two TAK-875-based pharmacophore models were identified using PHARMIT and employed. Virtual screening was performed via molecular docking with GNINA (validated by an RMSD of 1.48 Å against TAK-875’s crystallographic pose). Candidates were evaluated using ADMET predictions (ADMETLab). The most promising complexes from each pharmacophore underwent molecular dynamics (MD) simulations with GROMACS, analyzing RMSD, RMSF, PCA, and free energy landscapes. The first pharmacophore identified MOL1, MOL2, and MOL3 with superior affinities (−10.75 to −10.71 kcal mol⁻¹) compared to TAK-875 (−9.94 kcal mol⁻¹). However, all exhibited high toxicological risks (DILI ≈0.998; H-Hep ≈0.947), similar to the reference. The second pharmacophore revealed moderately affine candidates: MOL23 (−6.77 kcal mol⁻¹) stood out for its low predicted DILI (≈0.058) and lack of OATP inhibition, evading TAK 875’s toxic mechanism; MOL90 (−8.82 kcal mol⁻¹) inhibited OATP, showing elevated risk; MOL65 (−6.92 kcal mol⁻¹) displayed genotoxicity. MD simulations indicated that MOL1 induced significant conformational reorganization (higher mean RMSD vs. APO) and stabilized a distinct energy minimum, suggesting a putative allosteric effect. MOL23 exhibited moderate reorganization (RMSD intermediate between APO and MOL1), with partial stabilization at residue 150 and occupancy of transitional conformational states, compatible with a distinct putative allosteric modulation. The study identified MOL23 as a viable candidate, combining low hepatic risk, absence of OATP inhibition, and putative effective allosteric modulation. While high-affinity candidates (MOL1-3) replicated TAK-875’s toxicity, MOL23 offers a potential safe alternative for developing FFAR1-based antidiabetic therapies.