期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 37, 期 6, 页码 1628-1640出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2018.1462735
关键词
FXR alpha; antagonist; NDB; molecular dynamics simulation; binding free energy calculation
资金
- Natural Science Foundation of Shandong Province, China [ZR2018QB004]
- Talents of High Level Scientific Research Foundation of Qingdao Agricultural University [6631113318]
- open topic of Shanghai Key Laboratory of Plant Functional Genomics and Resources (Shanghai Chenshan Botanical Garden) [PFGR201702]
Farnesoid X receptor alpha (FXR alpha) is a bile acid-activated transcription factor, which plays important roles in the regulation of multiple metabolic processes. Development of FXR antagonist has revealed great potential for the treatment of metabolic disorders. The compound N-Benzyl-N-(3-(tertbutyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino). Benzamide (NDB) was recently determined as a selective antagonist of FXR alpha, while the detailed interaction mechanism is not well understood. In this study, the combined computational methods including molecular dynamics simulations, binding free energy calculation, and principal component analysis were utilized to investigate the effect of NDB on the dynamics behaviors and dimerization of FXR alpha The binding free energy calculation indicated that the protein dimerization increases NDB affinity and the binding of NDB also stabilizes the interaction between two subunits of FXR alpha. Further decomposition of the overall binding free energies into individual residues identifies several residues significant for NDB binding, including Leu291, Met294, Ala295, His298, Met332, Ser336, Ala452, and Leu455. It also suggests that the interactions of L289(A)-W458(B), W458(A)-L289(B), R459(A)-N461(B), and N461(A)-R459(B) are important for the dimer stabilization. This study provides a molecular basis for the understanding of binding mechanism between antagonist NDB and FXR alpha and valuable information for the novel FXR modulators design for the treatment of metabolic syndrome.
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