高级检索

  • ISSN 1006-3080
  • CN 31-1691/TQ

Linker Library: 基于几何特征的骨架跃迁片段库

李璐 廖奕晨 沈子豪 李洪林 李诗良

李璐, 廖奕晨, 沈子豪, 李洪林, 李诗良. Linker Library: 基于几何特征的骨架跃迁片段库[J]. 华东理工大学学报(自然科学版). doi: 10.14135/j.cnki.1006-3080.20220418002
引用本文: 李璐, 廖奕晨, 沈子豪, 李洪林, 李诗良. Linker Library: 基于几何特征的骨架跃迁片段库[J]. 华东理工大学学报(自然科学版). doi: 10.14135/j.cnki.1006-3080.20220418002
LI Lu, LIAO Yichen, SHEN Zihao, LI Honglin, LI Shiliang. Linker Library: Fragment Library for Scaffold Hopping Based on Geometric Features[J]. Journal of East China University of Science and Technology. doi: 10.14135/j.cnki.1006-3080.20220418002
Citation: LI Lu, LIAO Yichen, SHEN Zihao, LI Honglin, LI Shiliang. Linker Library: Fragment Library for Scaffold Hopping Based on Geometric Features[J]. Journal of East China University of Science and Technology. doi: 10.14135/j.cnki.1006-3080.20220418002

Linker Library: 基于几何特征的骨架跃迁片段库

doi: 10.14135/j.cnki.1006-3080.20220418002
基金项目: 国家自然科学基金面上项目(82173690)
详细信息
    作者简介:

    李璐:李 璐(1994-),女,湖北咸宁人,硕士生,主要研究方向为计算机辅助药物设计。E-mail:lilu_dws_llm@163.com

    通讯作者:

    李诗良,E-mail: shiliangli@ecust.edu.cn

  • 中图分类号: TP392

Linker Library: Fragment Library for Scaffold Hopping Based on Geometric Features

  • 摘要: 骨架跃迁是目前应用最广泛的药物设计策略之一,但是现有骨架跃迁方法产生的化合物大多为已报道的先导化合物的衍生物或类似物,化学结构缺乏新颖性。针对现有骨架跃迁方法的局限性,首次提出一种保持药效团与骨架之间的相对距离和角度不变的骨架跃迁策略,构建一个包含骨架几何特征的linker片段库:Linker Library。该片段库可以根据骨架中心到连接点之间距离和角度,推荐结构新颖且可保持官能团相对位置的片段,有助于指导化合物的骨架跃迁并加速药物发现进程。

     

  • 图  1  Linker Library的流程图

    Figure  1.  Flow chart of Linker Library

    图  2  RECAP中定义的11种拆分规则[21]

    Figure  2.  Eleven default bond cleavage types[21]

    图  3  不同数目连接点片段分布

    Figure  3.  The distribution of different number of connection points

    图  4  连接点“*”坐标生成的过程

    Figure  4.  The process of generating the coordinates of connection point "*"

    图  5  几何特征描述符——距离和角度

    Figure  5.  The geometric features descriptors-distances and angles

    图  6  几何特征字符串

    Figure  6.  The string of geometric features descriptors

    图  7  片段几何特征信息的储存

    Figure  7.  The storage of fragment geometric feature information

    图  8  Skepinone-L基于Linker Library的骨架跃迁

    Figure  8.  The scaffold hopping based on Linker Library of Skepinone-L

    表  1  新化合物与Skepinone-L的相似性比较

    Table  1.   Comparison of similarity between the new compounds and Skepinone-L

    NameHybridScoreShapeScoreFeatureScore
    11.0620.778 30.283 5
    21.1580.741 80.416 3
    31.1280.681 80.445 8
    40.764 60.5850.179 6
    51.170.738 50.431 6
    61.0540.780 70.273 4
    71.1650.706 90.457 7
    80.916 60.639 50.277 1
    90.877 30.640 60.236 7
    100.963 50.755 80.207 7
    下载: 导出CSV

    表  2  本文构建片段库与其他数据库的对比

    Table  2.   Comparison of difference between the fragment library and other databases

    ProgramData SourcesRulesFragment TypeAmount
    CAVEATCSD, PDB, CAST-3D, CONCORDThe vectors of connection bonds3D834197
    FDB-17GDB-17molecular size, polarity, and stereochemical complexity2D10 million
    ADMEToptChEMBL, EnamineADMET: Drug-likeness, comprising absorption, distribution, metabolism, excretion, and toxicity properties2D50 000
    PADFragDrugBank, PDBbind, PDB, Alan WoodRo3: a low molecular weight (MW) ≤ 300 Da, a reduced lipophily index clogP ≤ 3, a number of hydrogen bond donors and acceptors ≤3, low flexibility represented by a number of rotatable bonds ≤3 and a polar surface area (PSA) ≤ 60 A˚3D5919
    e-Drug3DFAD approved drugsThe calculation of the most probable tautomeric and ionic states at pH 7.4; The generation of multiple conformations for ring systems3D1305
    Linker LibraryCSDThe geometric features: the distances and angles between the pharmacophores and the skeleton3D1587020
    下载: 导出CSV
  • [1] NORMAN G. Drugs, devices, and the FDA: Part 1: An overview of approval processes for drugs[J]. JACC:Basic to Translational Science, 2016, 1(3): 170-179. doi: 10.1016/j.jacbts.2016.03.002
    [2] SCOTT M, ANN B. Drug discovery-an operating model for a new era[J]. Nature Biotechnology, 2001, 19(8): 727-730. doi: 10.1038/90765
    [3] VOUTCHKOVA A V, OSIMITZ T G, ANASTAS P T. Toward a comprehensive molecular design framework for reduced hazard[J]. Chemical Reviews, 2010, 110(10): 5845-5882. doi: 10.1021/cr9003105
    [4] SCHNEIDER G, NEIDHART W, GILLER T, et al. "Scaffold-hopping" by topological pharmacophore search: A contribution to virtual screening[J]. Angewandte Chemie International Edition, 1999, 38(19): 2894-2896. doi: 10.1002/(SICI)1521-3773(19991004)38:19<2894::AID-ANIE2894>3.0.CO;2-F
    [5] BOHM H J, FLOHR A, STAHL M. Scaffold hopping[J]. Drug discovery today technologies, 2004, 1(3): 217-224. doi: 10.1016/j.ddtec.2004.10.009
    [6] CRAMER R D, JILEK R J, GUESSREGEN S, et al. "Lead hopping". Validation of topomer similarity as a superior predictor of similar biological activities[J]. Journal of Medicinal Chemistry, 2004, 47(27): 6777-6791. doi: 10.1021/jm049501b
    [7] BROWN N, JACOBY E. On scaffolds and hopping in medicinal chemistry[J]. Mini Reviews in Medicinal Chemistry, 2006, 6(11): 1217-1229. doi: 10.2174/138955706778742768
    [8] MARTIN Y, MUCHMORE S. Beyond QSAR: Lead hopping to different structures[J], QSAR & Combinatorial Science, 2009, 28(8): 797-801.
    [9] MAUSER H, GUBA W. Recent developments in de novo design and scaffold hopping[J]. Current Opinion in Drug Discovery & Development, 2008, 11(3): 365-374.
    [10] SCHNEIDER G, SCHNEIDER P, RENNER S. Scaffold-hopping: How far can you jump?[J]. QSAR & Combinatorial Science, 2006, 38(15): 1162-1171.
    [11] LAURI G, BARTLETT P A. CAVEAT: A program to facilitate the design of organic molecules[J]. Journal of Computer-Aided Molecular Design, 1994, 8(1): 51-66. doi: 10.1007/BF00124349
    [12] MAASS P, SCHULZ G T, STAHL M, et al. Recore: A fast and versatile method for scaffold hopping based on small molecule crystal structure conformations[J]. Journal of Chemical Information & Modeling, 2007, 47(2): 390-399.
    [13] BERGMANN R, LINUSSON A, ZAMORA I. SHOP: Scaffold hopping by GRID-based similarity searches[J]. Journal of Medicinal Chemistry, 2007, 50(11): 2708-2717. doi: 10.1021/jm061259g
    [14] STUDIO D. Accelrys releases latest Discovery Studio simulator[J]. Medical Device Daily, 2012.
    [15] JIA H, DAI G X, SU W G, et al. Discovery, optimization and evaluation of potent and highly selective PI3Kγ−PI3Kδ dual inhibitors[J]. Journal of Medicinal Chemistry, 2019, 62(10): 4936-4948. doi: 10.1021/acs.jmedchem.8b02014
    [16] BROOD, Version 1.8. OpenEye Scientific Software, Inc. , Santa Fe, NM, USA. 2010. http://www.eyesopen.com/
    [17] SPARK, version 10.5. 6. Cresset, Litlington, Cambridgeshire, UK. 2020. https://www.cresset-group.com/software/spark/.
    [18] YANG H B, SUN L X, WANG Z, et al. ADMETopt: A web server for ADMET optimization in drug design via scaffold hopping[J]. Journal of Chemical Information and Modeling, 2018, 58(10): 2051-2056. doi: 10.1021/acs.jcim.8b00532
    [19] GastroPlus, Verision 9.0. Simulation software for drug discovery and development—manual. Simulations Plus, Inc, Lancaster, CA. 2020. https://www.simulations-plus.com.
    [20] ALLEN F H, BATTLE G M, ROBERTSON S. The cambridge crystallographic data base[J]. Computer Physics Communications, 1984, 33(1): 71-78.
    [21] LEWELL X Q, JUDD D B, WATSON S P, et al. RECAP - retrosynthetic combinatorial analysis procedure: A powerful new technique for identifying privileged molecular fragments with useful applications in combinatorial chemistry[J]. Journal of Chemical Information and Computer Sciences, 1998, 38(3): 511-522. doi: 10.1021/ci970429i
    [22] KOEBERLE S C, ROMIR J, FISCHER S, et al. Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor[J]. Nature Chemical Biology, 2011, 8(2): 141-143.
    [23] LIU X F, JIANG H L, LI H L. 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
    [24] VISINI R, AWALE M, REYMOND J L. Fragment database FDB-17[J]. Journal of Chemical Information & Modeling, 2017, 57(4): 700-709.
    [25] YANG J F, WANG F, JIANG W, et al. PADFrag: A database built for the exploration of bioactive fragment space for drug discovery[J]. Journal of Chemical Information and Modeling, 2018, 58(9): 1725-1730. doi: 10.1021/acs.jcim.8b00285
    [26] PIHAN E, COLLIANDRE L, GUICHOU J F, et al. e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design[J]. Bioinformatics, 2012, 28(11): 1540-1541. doi: 10.1093/bioinformatics/bts186
  • 加载中
图(8) / 表(2)
计量
  • 文章访问数:  9
  • HTML全文浏览量:  4
  • PDF下载量:  2
  • 被引次数: 0
出版历程
  • 收稿日期:  2022-04-18
  • 网络出版日期:  2022-08-23

目录

    /

    返回文章
    返回