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Molecular dynamics simulation study of IDH1R132H mutant protein and its inhibitor AG-881
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Ting-ting SHAO1, 2, Xiao-hua KONG2, Jing JIN2, 3, Fan-cui MENG2, 3, 4, Wei LIU2, 3, 4
Chinese Journal of New Drugs | 2023, 32(6) : 610 - 617
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Chinese Journal of New Drugs | 2023, 32(6): 610-617
Molecular dynamics simulation study of IDH1R132H mutant protein and its inhibitor AG-881
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Ting-ting SHAO1, 2, Xiao-hua KONG2, Jing JIN2, 3, Fan-cui MENG2, 3, 4, Wei LIU2, 3, 4
Affiliations
  • 1Pharmacy College, Tianjin Medical University, Tianjin 300070, China
  • 2Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300450, China
  • 3State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300301, China
  • 4Tianjin Institute of Pharmaceutical Research, Research Unit for Drug Metabolism, Chinese Academy of Medical Sciences, Tianjin 300301, China
Published: 2023-03-30
Outline
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Objective:

To investigate the mechanism of compound AG-881 on inhibiting IDH1R132H mutant protein by molecular dynamics method.

Methods:

The activated IDH1R132H protein structure and inactivated AG-881-IDH1R132H protein structure were constructed respectively and placed in a stereoscopic box. Molecular dynamics simulations were carried out on each system for 100 ns. The protein conformations of different systems were compared, and hydrogen bond analysis, energy analysis and principal component analysis (PCA), etc. were performed.

Results:

Substrate α-KG could stabilize IDH1R132H protein in the activated closed conformation. After AG-881 acted on the allosteric site of the protein at dimer interface, it made IDH1R132H in the open conformation of inactive state. In this process, amino acid residue Gln277 participated into the binding of AG-881. At the same time, hydrophobic occupation and hydrogen bond contributed mainly to the binding of AG-881 to IDH1R132H. In addition, halogen bond also played a certain role.

Conclusion:

Molecular dynamics simulation can be used as an effective aid for allosteric inhibitor design, and the potential mechanism of AG-881 inhibiting IDH1R132H activity can be studied, which can further provide theoretical guidance for the development of new drugs targeting IDH1 mutant proteins.

isocitrate dehydrogenase 1  /  molecular dynamics  /  AG-881  /  amino acid residue  /  allosteric site
Ting-ting SHAO, Xiao-hua KONG, Jing JIN, Fan-cui MENG, Wei LIU. Molecular dynamics simulation study of IDH1R132H mutant protein and its inhibitor AG-881[J]. Chinese Journal of New Drugs, 2023 , 32 (6) : 610 -617 .
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Year 2023 volume 32 Issue 6
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Article Info
  • Online Date：2026-03-06
  • Published：2023-03-30
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History
  • Accepted：2022-09-02
Funding
Affiliations
    1Pharmacy College, Tianjin Medical University, Tianjin 300070, China
    2Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300450, China
    3State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300301, China
    4Tianjin Institute of Pharmaceutical Research, Research Unit for Drug Metabolism, Chinese Academy of Medical Sciences, Tianjin 300301, China
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表12种不同金属材料的力学参数
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小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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