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

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

华东理工大学药学院, 上海市新药设计重点实验室, 上海200237

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
计量
- 文章访问数: 158
- HTML全文浏览量: 134
- PDF下载量: 22
- 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

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

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

摘要

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。
- 骨架跃迁 /
- 几何特征 /
- 片段库 /
- Linker Library /
- 药物设计
Abstract: In order to improve the success rate of new drugs, major pharmaceutical companies are committed to developing new strategies and technologies for Computer Aided Drug Design (CADD), Scaffold hopping is one of the most commonly used strategies for discovering lead compounds. However, most of the lead compounds generated by existing scaffold hopping strategies are derivatives or analogs of reported lead compounds that lack novelty. To improve structure novelty, we proposed a geometry-based scaffold hopping strategy, which takes the idea for the first time to keep the relative distances and angles unchanged between pharmacophores and skeleton. Thus, a linker library for scaffold hopping based on geometric features was constructed. The original compounds of the linker library were derived from Cambridge Structural Database (CSD), and which were broken into fragments by Retrosynthetic Combinatorial Analysis Procedure (RECAP). After a series of screening and processing, we designed a linker library containing 1587020 fragments with 2~4 connection points. There was a case about Skepinone-L, a selective inhibitor of MAPK11, which verified the usefulness of the linker library. Based on the distances and angles between the center to connected points of the skeleton, the linker library could recommend fragments with novel scaffolds to maintain the relative position of pharmacophores, which is beneficial to guide scaffold hopping and accelerate the process of drug discovery.
- scaffold hopping /
- geometric features /
- fragment library /
- linker Library /
- drug design

HTML全文

图 1 Linker Library的流程图

Figure 1. Flow chart of Linker Library

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图 2 RECAP中定义的11种拆分规则^[21]

Figure 2. Eleven default bond cleavage types^[21]

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图 3 不同数目连接点片段分布

Figure 3. Distribution of different number of connection points

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图 4 连接点“*”坐标生成的过程

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

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图 5 几何特征描述符

Figure 5. The geometric features descriptors

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图 6 几何特征字符串

Figure 6. String of the geometric features descriptors

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图 7 片段几何特征信息的储存

Figure 7. The storage of fragment geometric feature information

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图 8 Skepinone-L基于Linker Library的骨架跃迁

Figure 8. Scaffold hopping based on the Linker Library of Skepinone-L

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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

Name	HybridScore	ShapeScore	FeatureScore
1	1.062 0	0.778 3	0.283 5
2	1.158 0	0.741 8	0.416 3
3	1.128 0	0.681 8	0.445 8
4	0.764 6	0.585 0	0.179 6
5	1.170 0	0.738 5	0.431 6
6	1.054 0	0.780 7	0.273 4
7	1.165 0	0.706 9	0.457 7
8	0.916 6	0.639 5	0.277 1
9	0.877 3	0.640 6	0.236 7
10	0.963 5	0.755 8	0.207 7

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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

Program	Data sources	Rules	Fragment type	Amount
CAVEAT	CSD, PDB, CAST-3D, CONCORD	The vectors of connection bonds	3D	834197
FDB-17	GDB-17	Molecular size, polarity, and stereochemical complexity	2D	1×10⁹
ADMETopt	ChEMBL, Enamine	ADMET: Drug-likeness, comprising absorption, distribution, metabolism, excretion, and toxicity properties	2D	50 000
PADFrag	DrugBank, PDBbind, PDB, Alan Wood	Ro3: A low molecular weight (M_w) ≤ 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) ≤ 6×10⁻⁹ m	3D	5919
e-Drug3D	FAD approved drugs	The calculation of the most probable tautomeric and ionic states at pH 7.4; The generation of multiple conformations for ring systems	3D	1305
Linker Library	CSD	The geometric features: Distances and angles between the pharmacophores and the skeleton	3D	1587020

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