Clustered distribution of natural product leads of drugs in the chemical space as influenced by the privileged target-sites

Scientific Reports
Lin TaoYu Zong Chen

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 demo...Continue Reading

References

Jul 19, 1996·Journal of Medicinal Chemistry·G W Bemis, M A Murcko
Oct 2, 2001·Medicinal Research Reviews·T N Thompson
Aug 23, 2002·Clinical Pharmacokinetics·Patric StenbergPer Artursson
Sep 5, 2002·Nature Reviews. Drug Discovery·Andrew L Hopkins, Colin R Groom
Nov 3, 2004·Nature Reviews. Drug Discovery·Colin R GardnerOrn Almarsson
Dec 17, 2004·Nature·Jon Clardy, Christopher Walsh
Dec 17, 2004·Nature·Christopher Lipinski, Andrew Hopkins
May 3, 2005·Nature Reviews. Drug Discovery·Daniel C Liebler, F Peter Guengerich
Jul 28, 2005·Journal of Chemical Information and Modeling·Alexander BöckerGisbert Schneider
Nov 23, 2005·Proceedings of the National Academy of Sciences of the United States of America·Marcus A KochHerbert Waldmann
Nov 29, 2005·Journal of Chemical Information and Modeling·Jeffrey W GoddenJürgen Bajorath
Mar 4, 2006·Science·Francesca D CiccarelliPeer Bork
Jul 15, 2006·Nature Biotechnology·Gaia V PaoliniAndrew L Hopkins
Oct 4, 2006·Nature Reviews. Drug Discovery·Peter ImmingAchim Meyer
Nov 30, 2006·Drug Discovery Today·Peter Willett
Dec 2, 2006·Nature Reviews. Drug Discovery·John P OveringtonAndrew L Hopkins
Jan 11, 2007·Nature Biotechnology·Alan C ChengEnoch S Huang
Feb 21, 2007·Journal of Natural Products·David J Newman, Gordon M Cragg
Apr 19, 2007·Journal of Natural Products·Josefin LarssonAnders Backlund
May 29, 2007·Molecular Pharmaceutics·Sanjivanjit K BhalGreg M Pearl
Jun 20, 2007·Nature Chemical Biology·Barrie Wilkinson, Jason Micklefield
Feb 16, 2008·Drug Discovery Today·Arvind Saklani, Samuel K Kutty
Apr 15, 2008·Drug Discovery Today·Giulio VistoliBernard Testa
Oct 22, 2008·Nature Chemical Biology·Benoit BilangesBart Vanhaesebroeck
Mar 24, 2009·Journal of Chemical Information and Modeling·Narender SinghJose L Medina-Franco
Jun 2, 2009·Nature Chemical Biology·Jérôme HertBrian K Shoichet
Jun 30, 2009·Nature Chemical Biology·Stefan WetzelHerbert Waldmann
Jul 11, 2009·Science·Jesse W-H Li, John C Vederas
Feb 20, 2010·Nature Reviews. Drug Discovery·Steven M PaulAaron L Schacht
Mar 23, 2011·Journal of Computational Chemistry·Chun Wei Yap
Nov 1, 2009·Future Medicinal Chemistry·David J Newman, Gordon M Cragg
Jul 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Feng ZhuYuzong Chen
Aug 2, 2011·Nature Reviews. Drug Discovery·Mathias Rask-AndersenHelgi B Schiöth
Aug 20, 2011·Current Topics in Medicinal Chemistry·Ferran BriansóJordi Mestres
Nov 1, 2011·Angewandte Chemie·Stefan WetzelHerbert Waldmann
Jan 25, 2012·Nature Chemistry·Claudio AquinoGlenn C Micalizio
Jan 25, 2012·Nature Chemistry·G Richard BickertonAndrew L Hopkins
Feb 10, 2012·Journal of Natural Products·David J Newman, Gordon M Cragg

❮ Previous
Next ❯

Citations

Jul 29, 2016·Scientific Reports·Madeleine ErnstNina Rønsted
Oct 25, 2017·Medicinal Research Reviews·Gang Li, Hong-Xiang Lou
Jul 21, 2017·Journal of Agricultural and Food Chemistry·Lin TaoYu Zong Chen

❮ Previous
Next ❯

Software Mentioned

Scaffold Tree
Pubchem
Corina
iTOL
MODEL
gplots
Scaffold hunter
Phylocom
Matlab
PaDEL

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.