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 vi
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- 作者：Raman Sharma ; Alexandre S. Lawrenson ; Nicholas E. Fisher ; Ashley J. Warman ; Alison E. Shone ; Alasdair Hill ; Alison Mbekeani ; Chandrakala Pidathala ; Richard K. Amewu ; Suet Leung ; Peter Gibbons ; David W. Hong ; Paul Stocks ; Gemma L. Nixon ; James Chadwick ; Joanne Shearer ; Ian Gowers ; David Cronk ; Serge P. Parel ; Paul M. O'Neill ; Stephen A. Ward ; Giancarlo A. Biagini ; Neil G. Berry
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：April 12, 2012
- 年：2012
- 卷：55
- 期：7
- 页码：3144-3154
- 全文大小：333K
- 年卷期：v.55,no.7(April 12, 2012)
- ISSN：1520-4804
文摘
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 IC50 values ranging from 100 nM to 40 渭M 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.