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  • ISSN 1006-3080
  • CN 31-1691/TQ

ChemCloser:一个基于路径与片段匹配的药物设计软件

汪伟亮 邓卫平

汪伟亮, 邓卫平. ChemCloser:一个基于路径与片段匹配的药物设计软件[J]. 华东理工大学学报(自然科学版), 2021, 47(3): 278-283. doi: 10.14135/j.cnki.1006-3080.20200310004
引用本文: 汪伟亮, 邓卫平. ChemCloser:一个基于路径与片段匹配的药物设计软件[J]. 华东理工大学学报(自然科学版), 2021, 47(3): 278-283. doi: 10.14135/j.cnki.1006-3080.20200310004
WANG Weiliang, DENG Weiping. ChemCloser: A Drug Designing Software Based on Route and Fragment Matching[J]. Journal of East China University of Science and Technology, 2021, 47(3): 278-283. doi: 10.14135/j.cnki.1006-3080.20200310004
Citation: WANG Weiliang, DENG Weiping. ChemCloser: A Drug Designing Software Based on Route and Fragment Matching[J]. Journal of East China University of Science and Technology, 2021, 47(3): 278-283. doi: 10.14135/j.cnki.1006-3080.20200310004

ChemCloser:一个基于路径与片段匹配的药物设计软件

doi: 10.14135/j.cnki.1006-3080.20200310004
详细信息
    作者简介:

    汪伟亮(1981-),男,博士生,研究方向:药物化学。E-mail:332002351@qq.com

  • 中图分类号: TP319

ChemCloser: A Drug Designing Software Based on Route and Fragment Matching

  • 摘要: 根据先导化合物设计“me-too”药物可以显著降低新药开发的难度,提高开发效率和成功率。如何确切把握先导化合物的空间结构,设计结构新颖、价键合理、空间结构与先导化合物相同或相似的骨架是设计“me-too”药物的关键问题。设计并编写了一个可以提取结构式的长链,用已知的简单片段对长链进行匹配,最后进行拼接的全新药物骨架设计软件:ChemCloser。该软件能为研究人员提供结构合理、与先导化合物具有相同或相似的空间结构的所有核心骨架。

     

  • 图  1  ChemCloser的流程图

    Figure  1.  Flow chart of ChemCloser

    图  2  提取化合物1的长链并进行片段拼接

    Figure  2.  Extract the long chain of compound 1 and perform fragment splicing

    图  3  化合物5(a)和化合物6(b)的化学结构式

    Figure  3.  Chemical structure of compound 5(a) and compound 6(b)

    表  1  ChemCloser生成的新结构与化合物1的结构相似性

    Table  1.   Similarity between the new structure generated by ChemCloser and the structure of compound 1

    IndexScore rangeStructure numbersPercentage of total
    structure numbers/%
    10.90 ~ 1.008 55030.2
    20.80 ~ 0.8911 56040.9
    30.70 ~ 0.794 19014.8
    40.60 ~ 0.692 6009.2
    50.50 ~ 0.593861.4
    下载: 导出CSV

    表  2  基于化合物56生成的新结构的相似性值分布

    Table  2.   Similarity value distribution of the new generated structures based on compound 5 and 6

    Score rangePercentage of total structure numbers/%
    Compared with compound 5Compared with compound 6a)Compared with compound 6b)Compared with compound 6c)
    0.90 ~ 1.0058.4036.900
    0.80 ~ 0.905.5062.501.16
    0.70 ~ 0.800.20074.024.3
    The start and end atom numbers of the long chain in compound 6 are: a) 28、29; b) 1、28; c) 1、21, respectively
    下载: 导出CSV
  • [1] PAUL S M, MYTELKA D S, DUNWIDDIE C T, et al. How to improve R&D productivity: The pharmaceutical industry's grand challenge[J]. Nature Reviews Drug Discovery, 2010, 9: 203-214. doi: 10.1038/nrd3078
    [2] AVORN J. The $2.6 billion pill: Methodologic and policy considerations[J]. The New England Journal of Medicine, 2015, 372(20): 1877-1879. doi: 10.1056/NEJMp1500848
    [3] BOHM H J. The computer program LUDI: A new method for the de novo design of enzyme inhibitors[J]. Journal of Computer-Aided Molecular Design, 1992, 6: 61-78. doi: 10.1007/BF00124387
    [4] DOUGUETD D, MUNIER-LEHMANN H, LABESSE G, et al. LEA3D: A computer-aided ligand design for structure-based drug design[J]. Journal of Medicinal Chemistry, 2005, 48: 2457-2468. doi: 10.1021/jm0492296
    [5] WANG R X, GAO Y, LAI L H. LigBuilder: A multi-purpose program for structure-based drug design[J]. Journal of Molecular Modeling, 2000, 6(7): 498-516.
    [6] YUAN Y X, PEI J F, LAI L H. Ligbuilder2: A practical de novo drug design approach[J]. Journal of Chemical Information and Modeling, 2001, 51(5): 1083-1091.
    [7] NADERI M, ALVIN C, DING Y, et al. A graph-based approach to construct target-focused libraries for virtual screening[J]. Journal of Cheminformatics, 2016, 8(14): 1-16. doi: 10.1186/s13321-016-0126-6
    [8] NISHIBATA Y, ITAI A. Automatic creation of drug candidate structures based on receptor structure[J]. Tetrahedron, 1991, 47(43): 8985-8990. doi: 10.1016/S0040-4020(01)86503-0
    [9] GITLLET V, JOHNSON A P, MATA P, et al. SPROUT: A program for structure generation[J]. Journal of Computer-Aided Molecular Design, 1993, 7: 127-153. doi: 10.1007/BF00126441
    [10] BROWN N, MCKAY B, GILARDONI F, et al. A graph-based genetic algorithm and its application to the multiobjective evolution of median molecules[J]. Journal of Chemical Information and Computer Sciences, 2004, 44(30): 1079-1087. doi: 10.1021/ci034290p
    [11] FECHNER U, SCHNEIDER G. Flux (2): Comparison of molecular mutation and crossover operators for ligand-based de novo design[J]. Journal of Chemical Information and Modeling, 2007, 47(2): 656-667. doi: 10.1021/ci6005307
    [12] TAIRAN L, MISAGH N, CHRIS A, et al. Break down in order to build up: Decomposing small molecules for fragment-based drug design with eMolFrag[J]. Journal of Chemical Information and Modeling, 2017, 57(4): 627-631. doi: 10.1021/acs.jcim.6b00596
    [13] GHERSI D, SINGH M. molBLOCKS: Decomposing small molecule sets and uncovering enriched fragments[J]. Bioinformatics, 2014, 30(14): 2081-2083. doi: 10.1093/bioinformatics/btu173
    [14] MARTIN S, ANDY V. Scaffold hopping in medicinal chemistry [EB/OL]. (2013-11-01)[2015-08-28]. https://onlinelibrary.wiley.com/doi/book/10.1002/9783527665143.
    [15] LI S H, XU H, CUI S C, et al. Discovery and rational design of natural-product-derived 2-phenyl-3, 4-dihydro-2H-benzo [f] chromen-3-amine analogs as novel and potent dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes[J]. Journal of Medicinal Chemistry, 2016, 59 (14): 6772-6790.
    [16] LI S H, QIN C, CUI S C, et al. Discovery of a natural-product-derived preclinical candidate for once-weekly treatment of type 2 diabetes[J]. Journal of Medicinal Chemistry, 2019, 62 (5): 2348-2361.
    [17] LIU X, JIANG H, LI H. SHAFTS: A hybrid approach for 3D molecular similarity calculation: 1. Method and assessment of virtual screening[J]. Journal of Chemical Information and Modeling, 2011, 51(9): 2372-2385. doi: 10.1021/ci200060s
    [18] KOTALAR P R, BELLA J, OLSON N H, et al. Structural studies of two rhinovirus serotypes complexed with fragments of their cellular receptor[J]. The EMBO Journal, 1999, 18: 6249-6259. doi: 10.1093/emboj/18.22.6249
    [19] JOHNSON T W, RICHARDSON P F, BAILEY S, et al. Discovery of (10R)-7-Amino-12-fluoro-2,10,16-trimethyl-5-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4-(metheno)pyrazolo[4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations[J]. Journal of Medicinal Chemistry, 2014, 57(11): 4720-4744. doi: 10.1021/jm500261q
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出版历程
  • 收稿日期:  2020-03-10
  • 网络出版日期:  2020-05-26
  • 刊出日期:  2021-06-30

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