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ChemGPS-NPweb: chemical space navigation online
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
Uppsala University. (Biomedicinska centrum (BMC), BMC-intendenturen)
DECS Global Compound Sciences, AstraZeneca R&D, Mölndal.
DECS Global Compound Sciences, AstraZeneca R&D, Mölndal.
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2009 (English)In: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 23, no 4, 253-259 p.Article in journal (Refereed) Published
Abstract [en]

Internet has become a central source for information, tools, and services facilitating the work for medicinal chemists and drug discoverers worldwide. In this paper we introduce a web-based public tool, ChemGPS-NPWeb (http://chemgps.bmc.uu.se), for comprehensive chemical space navigation and exploration in terms of global mapping onto a consistent, eight dimensional map over structure derived physico-chemical characteristics. ChemGPS-NPWeb can assist in compound selection and prioritization; property description and interpretation; cluster analysis and neighbourhood mapping; as well as comparison and characterization of large compound datasets. By using ChemGPS-NPWeb, researchers can analyze and compare chemical libraries in a consistent manner. In this study it is demonstrated how ChemGPS-NPWeb can assist in interpreting results from two large datasets tested for activity in biological assays for pyruvate kinase and Bcl-2 family related protein interactions, respectively. Furthermore, a more than 30-year-old suggestion of “chemical similarity” between the natural pigments betalains and muscaflavins is tested.

Place, publisher, year, edition, pages
2009. Vol. 23, no 4, 253-259 p.
Keyword [en]
ChemGPS-NP, Natural products, Chemical space, Internet tool, Drug discovery, Biologically active compounds
National Category
Medicinal Chemistry
Research subject
Pharmacognosy
Identifiers
URN: urn:nbn:se:uu:diva-89345DOI: 10.1007/s10822-008-9255-yISI: 000263797300006PubMedID: 19082743OAI: oai:DiVA.org:uu-89345DiVA: diva2:160186
Available from: 2009-02-12 Created: 2009-02-12 Last updated: 2012-03-22Bibliographically 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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