Cargando…

Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites

Some natural product leads of drugs (NPLDs) have been found to congregate in the chemical space. The extent, detailed patterns, and mechanisms of this congregation phenomenon have not been fully investigated and their usefulness for NPLD discovery needs to be more extensively tested. In this work, w...

Descripción completa

Detalles Bibliográficos
Autores principales: Tao, Lin, Zhu, Feng, Qin, Chu, Zhang, Cheng, Chen, Shangying, Zhang, Peng, Zhang, Cunlong, Tan, Chunyan, Gao, Chunmei, Chen, Zhe, Jiang, Yuyang, Chen, Yu Zong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380136/
https://www.ncbi.nlm.nih.gov/pubmed/25790752
http://dx.doi.org/10.1038/srep09325
_version_ 1782519730105483264
author Tao, Lin
Zhu, Feng
Qin, Chu
Zhang, Cheng
Chen, Shangying
Zhang, Peng
Zhang, Cunlong
Tan, Chunyan
Gao, Chunmei
Chen, Zhe
Jiang, Yuyang
Chen, Yu Zong
author_facet Tao, Lin
Zhu, Feng
Qin, Chu
Zhang, Cheng
Chen, Shangying
Zhang, Peng
Zhang, Cunlong
Tan, Chunyan
Gao, Chunmei
Chen, Zhe
Jiang, Yuyang
Chen, Yu Zong
author_sort Tao, Lin
collection PubMed
description Some natural product leads of drugs (NPLDs) have been found to congregate in the chemical space. The extent, detailed patterns, and mechanisms of this congregation phenomenon have not been fully investigated and their usefulness for NPLD discovery needs to be more extensively tested. In this work, we generated and evaluated the distribution patterns of 442 NPLDs of 749 pre-2013 approved and 263 clinical trial small molecule drugs in the chemical space represented by the molecular scaffold and fingerprint trees of 137,836 non-redundant natural products. In the molecular scaffold trees, 62.7% approved and 37.4% clinical trial NPLDs congregate in 62 drug-productive scaffolds/scaffold-branches. In the molecular fingerprint tree, 82.5% approved and 63.0% clinical trial NPLDs are clustered in 60 drug-productive clusters (DCs) partly due to their preferential binding to 45 privileged target-site classes. The distribution patterns of the NPLDs are distinguished from those of the bioactive natural products. 11.7% of the NPLDs in these DCs have remote-similarity relationship with the nearest NPLD in their own DC. The majority of the new NPLDs emerge from preexisting DCs. The usefulness of the derived knowledge for NPLD discovery was demonstrated by the recognition of the new NPLDs of 2013–2014 approved drugs.
format Online
Article
Text
id pubmed-5380136
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-53801362017-04-11 Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites Tao, Lin Zhu, Feng Qin, Chu Zhang, Cheng Chen, Shangying Zhang, Peng Zhang, Cunlong Tan, Chunyan Gao, Chunmei Chen, Zhe Jiang, Yuyang Chen, Yu Zong Sci Rep Article Some natural product leads of drugs (NPLDs) have been found to congregate in the chemical space. The extent, detailed patterns, and mechanisms of this congregation phenomenon have not been fully investigated and their usefulness for NPLD discovery needs to be more extensively tested. In this work, we generated and evaluated the distribution patterns of 442 NPLDs of 749 pre-2013 approved and 263 clinical trial small molecule drugs in the chemical space represented by the molecular scaffold and fingerprint trees of 137,836 non-redundant natural products. In the molecular scaffold trees, 62.7% approved and 37.4% clinical trial NPLDs congregate in 62 drug-productive scaffolds/scaffold-branches. In the molecular fingerprint tree, 82.5% approved and 63.0% clinical trial NPLDs are clustered in 60 drug-productive clusters (DCs) partly due to their preferential binding to 45 privileged target-site classes. The distribution patterns of the NPLDs are distinguished from those of the bioactive natural products. 11.7% of the NPLDs in these DCs have remote-similarity relationship with the nearest NPLD in their own DC. The majority of the new NPLDs emerge from preexisting DCs. The usefulness of the derived knowledge for NPLD discovery was demonstrated by the recognition of the new NPLDs of 2013–2014 approved drugs. Nature Publishing Group 2015-03-20 /pmc/articles/PMC5380136/ /pubmed/25790752 http://dx.doi.org/10.1038/srep09325 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Tao, Lin
Zhu, Feng
Qin, Chu
Zhang, Cheng
Chen, Shangying
Zhang, Peng
Zhang, Cunlong
Tan, Chunyan
Gao, Chunmei
Chen, Zhe
Jiang, Yuyang
Chen, Yu Zong
Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites
title Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites
title_full Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites
title_fullStr Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites
title_full_unstemmed Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites
title_short Clustered Distribution of Natural Product Leads of Drugs in the Chemical Space as Influenced by the Privileged Target-Sites
title_sort clustered distribution of natural product leads of drugs in the chemical space as influenced by the privileged target-sites
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5380136/
https://www.ncbi.nlm.nih.gov/pubmed/25790752
http://dx.doi.org/10.1038/srep09325
work_keys_str_mv AT taolin clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT zhufeng clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT qinchu clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT zhangcheng clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT chenshangying clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT zhangpeng clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT zhangcunlong clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT tanchunyan clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT gaochunmei clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT chenzhe clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT jiangyuyang clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites
AT chenyuzong clustereddistributionofnaturalproductleadsofdrugsinthechemicalspaceasinfluencedbytheprivilegedtargetsites