Deciphering the Structural Determinants Critical in Attaining the FXR Partial Agonism

Elucidation of structural determinants is pivotal for structure-based drug discovery. The Farnesoid X receptor (FXR) is a proven target for NASH; however, its full agonism causes certain clinical complications. Therefore, partial agonism (PA) appears as a viable alternative for improved therapeutics. Since the agonist and PA both share the same binding site, i.e., ligand-binding pocket (LBP), which is highly dynamic and has synergy with the substrate binding site, the selective designing of PA is challenging. The identification of structural and conformational determinants is critical for PA compared with an agonist. Furthermore, the mechanism by which PA modulates the structural dynamics of FXR at the residue level, a prerequisite for PA designing, is still elusive. Here, by using ∼4.5 μs of MD simulations and residue-wise communication network analysis, we identified the structural regions which are flexible with PA but frozen with an agonist. Also, the network analysis identified the considerable changes between an agonist and PA in biologically essential zones of FXR such as helix H10/H11 and loop L:H11/H12, which lead to the modulation of synergy between LBP and the substrate binding site. Furthermore, the thermodynamic profiling suggested the methionine residues, mainly M³²⁸, M³⁶⁵, and M⁴⁵⁰, seem to be responsible for the recruitment of PA. The other residues I³⁵⁷, Y³⁶¹, L⁴⁶⁵, F³⁰⁸, Q³¹⁶, and K³²¹ are also identified, exclusively interacting with PA. This study offers novel structural and mechanistic insights that are critical for FXR targeted drug discovery for PA designing.