title: Clustered distribution of natural product leads of drugs in the chemical space as influenced by the privileged target-sites.
abstract: 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.
authors: 1] Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China [2] Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543 [3] NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456.
authors: Lin
authors: L
authors: Tao
authors: 1] Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China [2] Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543 [3] Innovative Drug Research Centre and College of Chemistry and Chemical Engineering, Chongqing University, Chongqing, P. R. China.
authors: Feng
authors: F
authors: Zhu
authors: 1] Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543 [2] NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456.
authors: Chu
authors: C
authors: Qin
authors: Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543.
authors: Cheng
authors: C
authors: Zhang
authors: Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543.
authors: Shangying
authors: S
authors: Chen
authors: Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543.
authors: Peng
authors: P
authors: Zhang
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China.
authors: Cunlong
authors: C
authors: Zhang
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China.
authors: Chunyan
authors: C
authors: Tan
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China.
authors: Chunmei
authors: C
authors: Gao
authors: Zhejiang Key Laboratory of Gastro-intestinal Pathophysiology, Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, P. R. China.
authors: Zhe
authors: Z
authors: Chen
authors: Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China.
authors: Yuyang
authors: Y
authors: Jiang
authors: 1] Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, the Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology, the Graduate School at Shenzhen, Tsinghua University, Shenzhen, and Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, PO Box 518000, P. R. China [2] Bioinformatics and Drug Design Group, Department of Pharmacy, and Center for Computational Science and Engineering, National University of Singapore, Singapore 117543 [3] NUS Graduate School for Integrative Sciences and Engineering, Singapore 117456.
authors: Yu Zong
authors: YZ
authors: Chen
mesh_terms: D001688:Biological Products / Q000737:chemistry*; D055808:Drug Discovery; D015394:Molecular Structure
chemical_list: D001688:Biological Products