Multi-model in silico characterization of 3-benzamidobenzoic acid derivatives as partial agonists of Farnesoid X receptor in the management of NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a pathological condition which is strongly correlated with fat accumulation in the liver that has become a major health hazard globally. So far, limited treatment options are available for the management of NAFLD and partial agonism of Farnesoid X receptor (FXR) has proven to be one of the most promising strategies for treatment of NAFLD. In present work, a range of validated predictive cheminformatics and molecular modeling studies were performed with a series of 3-benzamidobenzoic acid derivatives in order to recognize their structural requirements for possessing higher potency towards FXR. 2D-QSAR models were able to extract the most significant structural attributes determining the higher activity towards the receptor. Ligand-based pharmacophore model was created with a novel and less-explored open access tool named QPhAR to acquire information regarding important 3D-pharmacophoric features that lead to higher agonistic potential towards the FXR. The alignment of the dataset compounds based on pharmacophore mapping led to 3D-QSAR models that pointed out the most crucial steric and electrostatic influence. Molecular dynamics (MD) simulation performed with the most potent and the least potent derivatives of the current dataset helped us to understand how to link the structural interpretations obtained from 2D-QSAR, 3D-QSAR and pharmacophore models with the involvement of specific amino acid residues in the FXR protein. The current study revealed that hydrogen bond interactions with carboxylate group of the ligands play an important role in the ligand receptor binding but higher stabilization of different helices close to the binding site of FXR (e.g., H5, H6 and H8) through aromatic scaffolds of the ligands should lead to higher activity for these ligands. The present work affords important guidelines towards designing novel FXR partial agonists for new therapeutic options in the management of NAFLD. Moreover, we relied mainly on open-access tools to develop the in-silico models in order to ensure their reproducibility as well as utilization. [Display omitted] •Partial agonism of FXR is a promising strategy for the treatment of NAFLD.•A series of 3-benzamidobenzoic acid derivatives were used for in silico analyses.•2D- and 3D-QSAR provided crucial information regarding structural requirements.•Ligand-based pharmacophore mapping highlighted important pharmacophore features.•MD simulation depicted crucial ligand