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

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

汪伟亮^,,
邓卫平

华东理工大学药学院，上海新药设计重点实验室，上海 200237

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
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- PDF下载量: 19
- 被引次数: 0
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

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

WANG Weiliang^,,
DENG Weiping

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

摘要

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。
- “me-too”药物 /
- 长链提取 /
- 片段拼接 /
- 软件 /
- ChemCloser
Abstract: New drug design is a huge project, and the failure rate is very high. On the basis of the existing active compounds, the design of "me-too" drugs can increase the success rate. The lead compound can provide the same or similar spatial structure as the original active compound, and a novel skeleton. However, the skeleton of the lead compounds needn't have good physicochemical properties. Designing "me-too" drugs based on lead compounds can significantly reduce the difficulty of new drug development and improve the development efficiency and success rate. How to accurately grasp the spatial structure of the lead compounds, designing a novel structure, a reasonable valence bond, and a skeleton with the same or similar spatial structure as the lead compound are the key issues for the design of "me-too" drugs. We design and write an automated new drug skeleton design software based on the extraction of structural long chains, fragment matching and splicing: ChemCloser. The software can provide researchers with all core frameworks with reasonable structure and the same or similar spatial structure as the lead compounds. Researchers may find frameworks with novel structures, good physical properties and stable chemical properties in these core frameworks. After splicing pharmacodynamic groups on these skeletons, it can produce the same or similar biological activity as the original active compound.
- “me-too” drugs /
- long chain extraction /
- fragment splicing /
- software /
- ChemCloser

HTML全文

图 1 ChemCloser的流程图

Figure 1. Flow chart of ChemCloser

下载: 全尺寸图片幻灯片

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

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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)

下载: 全尺寸图片幻灯片

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

Index	Score range	Structure numbers	Percentage of total structure numbers/%
1	0.90 ~ 1.00	8 550	30.2
2	0.80 ~ 0.89	11 560	40.9
3	0.70 ~ 0.79	4 190	14.8
4	0.60 ~ 0.69	2 600	9.2
5	0.50 ~ 0.59	386	1.4

下载: 导出CSV

表 2 基于化合物5和6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 range	Percentage of total structure numbers/%
Score range	Compared with compound 5	Compared with compound 6^a)	Compared with compound 6^b)	Compared with compound 6^c)
0.90 ~ 1.00	58.40	36.9	0	0
0.80 ~ 0.90	5.50	62.5	0	1.16
0.70 ~ 0.80	0.20	0	74.0	24.3
The start and end atom numbers of the long chain in compound 6 are: a) 28、29; b) 1、28; c) 1、21, respectively

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