Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum

Malaria Journal

Research

George Papadatos¹  Sandra Duffy²  Vicky M Avery²  David Waterson³  Jeremy N Burrows³  Paul Willis³  Thomas Spangenberg³  Yuvaraj Sambandan⁴  Shivendra Singh⁴  Sridevi Bashyam⁴  Shyni Puthukkuti⁴ 

[1] Computational Chemical Biology group, European Molecular Biology Laboaratory - European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Wellcome Trust Genome Campus, CB10 1SD, Hinxton, UK;Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, 4111, Nathan, QLD, Australia;Medicines for Malaria Venture MMV, PO Box 1826, ICC - Block G, 3rd Floor, route de Pré-Bois 20, 1215, Geneva 15, Switzerland;Syngene International Ltd, Plot No 2 & 3, Bommasandra IV Phase, Jigani Link Road, 560 100, Bangalore, India;

关键词: Chemical library;    High throughput screening;    Phenotypic;    Screening cascade;    Malaria;    Plasmodium;    Chemical diversity;    Hit validation;    Cluster;    Drug-like;    Cheminformatics;   

DOI  :  10.1186/1475-2875-13-190

 received in 2014-04-02, accepted in 2014-05-21,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundIn view of the need to continuously feed the pipeline with new anti-malarial agents adapted to differentiated and more stringent target product profiles (e.g., new modes of action, transmission-blocking activity or long-duration chemo-protection), a chemical library consisting of more than 250,000 compounds has been evaluated in a blood-stage Plasmodium falciparum growth inhibition assay and further assessed for chemical diversity and novelty.MethodsThe selection cascade used for the triaging of hits from the chemical library started with a robust three-step in vitro assay followed by an in silico analysis of the resulting confirmed hits. Upon reaching the predefined requirements for selectivity and potency, the set of hits was subjected to computational analysis to assess chemical properties and diversity. Furthermore, known marketed anti-malarial drugs were co-clustered acting as ‘signposts’ in the chemical space defined by the hits. Then, in cerebro evaluation of the chemical structures was performed to identify scaffolds that currently are or have been the focus of anti-malarial medicinal chemistry programmes. Next, prioritization according to relaxed physicochemical parameters took place, along with the search for structural analogues. Ultimately, synthesis of novel chemotypes with desired properties was performed and the resulting compounds were subsequently retested in a P. falciparum growth inhibition assay.ResultsThis screening campaign led to a 1.25% primary hit rate, which decreased to 0.77% upon confirmatory repeat screening. With the predefined potency (EC50 < 1 μM) and selectivity (SI > 10) criteria, 178 compounds progressed to the next steps where chemical diversity, physicochemical properties and novelty assessment were taken into account. This resulted in the selection of 15 distinct chemical series.ConclusionA selection cascade was applied to prioritize hits resulting from the screening of a medium-sized chemical library against blood-stage P. falciparum. Emphasis was placed on chemical novelty whereby computational clustering, data mining of known anti-malarial chemotypes and the application of relaxed physicochemical filters, were key to the process. This led to the selection of 15 chemical series from which ten confirmed their activity when newly synthesized sample were tested.

【 授权许可】

Unknown   
© Avery et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.