Farnesoid X Receptor Agonist as a new treatment option for Non-Alcoholic Fatty Liver disease: A Review

Singh, Sukhraj; Kharbanda, KK

doi:10.17352/ahr.000014

Cited by 1 publication

(1 citation statement)

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“…The ligand-activated transcription factor FXR encoded by gene NR1H4 is a member of the nuclear receptor (NR) superfamily. FXR acts as a cellular sensor for bile acids and plays a key role as a metabolic regulator and liver protector. , FXR agonists are emerging as effective potential therapies for treating individuals with NASH as they have beneficial effects on many aspects of the disease. − The whole NR family shares the overall architecture of the N-terminal region with a ligand-independent activation function (AF1), followed by a highly conserved zinc-finger DNA-binding domain (DBD), a flexible hinge region, and a ligand-binding domain (LBD) composed of 12 alpha helices (H1–H12). The LBD contains two well-conserved regions: a signature motif and the activation function 2 (AF2) motif located at the carboxy-terminal end of the domain, which is responsible for the ligand-dependent transactivation function. , The LBD is the molecular basis for FXR activation, causing a conformational change in the FXR in response to ligand binding, resulting in corepressor dissociation, coactivator association, and final regulation of target genes.…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Structural Determinants Critical in Attaining the FXR Partial Agonism

et al. 2023

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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.

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