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Identification of novel antimalarial chemotypes via chemoinformatic compound selection methods for a high-throughput screening program against the novel malarial target, PfNDH2: increasing hit rate via virtual screening methods.

Sharma, Raman, Lawrenson, Alexandre S, Fisher, Nicholas, Warman, Ashley, Shone, Alison, Hill, Alasdair, Mbekeani, Alison, Pidathala, Chandrakala, Amewu, Richard K, Leung, Suet, Gibbons, Peter, Hong, David W, Stocks, Paul A., Nixon, Gemma L, Chadwick, James, Shearer, Joanne, Gowers, Ian, Cronk, David, Parel, Serge P, O'Neill, Paul M, Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 and Berry, Neil G (2012) 'Identification of novel antimalarial chemotypes via chemoinformatic compound selection methods for a high-throughput screening program against the novel malarial target, PfNDH2: increasing hit rate via virtual screening methods.'. Journal of medicinal chemistry, Vol 55, Issue 7, pp. 3144-54.

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Abstract

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1021/jm3001482
Depositing User: Mary Creegan
Date Deposited: 02 Jan 2013 10:20
Last Modified: 06 Feb 2018 13:05
URI: http://archive.lstmed.ac.uk/id/eprint/3081

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