In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

01 Jul 2008

David Plouffe, Achim Brinker, Case McNamara, Kerstin Henson, Nobutaka Kato, Kelli Kuhen, Advait Nagle, Francisco Adrián, Jason T. Matzen, Paul Anderson, Tae-gyu Nam, Nathanael S. Gray, Arnab Chatterjee, Jeff Janes, S. Frank Yan, Richard Trager, Jeremy S. Caldwell, Peter G. Schultz, Yingyao Zhou and Elizabeth A. Winzeler

Proceedings of the National Academy of Sciences of the United States of America

DOI: 10.1073/pnas.0802982105

Published in PNAS, Novartis describe the first phenotypic screening of a pharmaceutical library against P. falciparum. This screening exercise led to the series within the Novartis-MMV miniportfolio that delivered preclinical and clinical candidates: NITD609 and GNF156. The data and structures of the confirmed, commercially available hits have been made available in the ChEMBL-NTD online database.

Abstract

The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust high-throughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of ≈1.7 million compounds, we identified a diverse collection of ≈6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 μM). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.

The full article can be viewed on the PNAS website.