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Deciphering the Structural Determinants Critical in Attaining the FXR Partial Agonism.
Kumari, Anita; Mittal, Lovika; Srivastava, Mitul; Pathak, Dharam Pal; Asthana, Shailendra.
Afiliação
  • Kumari A; Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana121001, India.
  • Mittal L; Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi110017, India.
  • Srivastava M; Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana121001, India.
  • Pathak DP; Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana121001, India.
  • Asthana S; Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), New Delhi110017, India.
J Phys Chem B ; 127(2): 465-485, 2023 01 19.
Article em En | MEDLINE | ID: mdl-36609158
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Citoplasmáticos e Nucleares / Descoberta de Drogas Idioma: En Revista: J Phys Chem B Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Citoplasmáticos e Nucleares / Descoberta de Drogas Idioma: En Revista: J Phys Chem B Ano de publicação: 2023 Tipo de documento: Article