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ChemGPS-NP: tuned for navigation in biologically relevant chemical space
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
2007 (English)In: Journal of natural products (Print), ISSN 0163-3864, E-ISSN 1520-6025, Vol. 70, no 5, 789-794 p.Article in journal (Refereed) Published
Abstract [en]

Natural compounds are evolutionary selected and prevalidated by Nature, displaying a unique chemical diversity and a corresponding diversity of biological activities. These features make them highly interesting for studies of chemical biology, and in the pharmaceutical industry for development of new leads. Of utmost importance, for the discovery of new biologically active compounds, is the identification and charting of the corresponding biologically relevant chemical space. The primary key to this is the coverage of the natural products' chemical space. Here we introduce ChemGPS-NP, a new tool tuned for handling the chemical diversity encountered in natural products research, in contrast to previous tools focused on the much more restricted drug-like chemical space. The aim is to provide a framework for making compound classification and comparison more efficient and stringent, to identify volumes of chemical space related to particular biological activities, and to track changes in chemical properties due to, for example, evolutionary traits and modifications in biosynthesis. Physical-chemical properties not directly discernible from structural data can be discovered, making selection more efficient and increasing the probability of hit generation when screening natural compounds and analogues.

Place, publisher, year, edition, pages
2007. Vol. 70, no 5, 789-794 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-16224DOI: 10.1021/np070002yISI: 000246764300013PubMedID: 17439280OAI: oai:DiVA.org:uu-16224DiVA: diva2:43995
Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2017-12-08Bibliographically approved
In thesis
1. ChemGPS-NP and the Exploration of Biologically Relevant Chemical Space
Open this publication in new window or tab >>ChemGPS-NP and the Exploration of Biologically Relevant Chemical Space
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chemical space is basically infinite, and comprises all molecules that could possibly exist. Intelligent ways to efficiently navigate through chemical space and to select promising compounds in drug discovery are important tasks, and the focus of this thesis.

In this work a new model for chemical space navigation, ChemGPS-NP, was developed. This model is based on a methodology where a global chemical space map is defined through principal component analysis of physico-chemical properties of a reference set of compounds. Through interpolation from the reference set, positions of novel compounds can be defined on this map and interpreted as chemical properties.

ChemGPS-NP was demonstrated to be able to chart the entire biologically relevant chemical space, including both drug-like and natural compounds. This is an important improvement considering the present interest in natural products (NPs) in the pharmaceutical industry, as well as the track record of NPs to serve as basis for more than 50% of all marketed drugs. ChemGPS-NP proved able to handle and process large data sets, to aid in efficient selection of test objects, and to extract useful information from the results of high-throughput screening campaigns. Using ChemGPS-NP, it was shown that NPs occupy unique regions of chemical property space in comparison to drug-like compounds, and a number of features distinguishing NPs from medicinal chemistry compounds were identified.

ChemGPS-NP was also shown to be able to reliably predict mode of action of anticancer agents based on chemical structure, a finding that has potential to improve cancer research efficiency. Applying a property based similarity search based on calculated eight dimensional Euclidean distances from ChemGPS-NP rendered a tool to identify NP inspired potential leads for drug discovery.

Furthermore, ChemGPS-NPWeb, an online version of ChemGPS-NP, was developed, which provides scientists with open access to the tool via http://chemgps.bmc.uu.se/.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 89
National Category
Pharmaceutical Sciences
Research subject
Pharmacognosy
Identifiers
urn:nbn:se:uu:diva-89364 (URN)978-91-554-7431-7 (ISBN)
Public defence
2009-03-27, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-03-04 Created: 2009-02-12 Last updated: 2009-09-04Bibliographically approved

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