Malaria Box supporting information

Data from the 20,000 hits

The full list of the 20,000 hits from Plasmodium falciparum (P. falciparum) whole cell screening originates from the GlaxoSmithKline Tres Cantos Antimalarial Set (TCAMS), Novartis-GNF Malaria Box Data set and St. Jude Children's Research Hospital’s Dataset available on the ChEMBL website. Additionally a small set of active compounds from commercially available libraries was added; this latter set has not previously been published. The Public Data Set (Excel file) contains the information pertaining to each compound: the index number, ChEMBL compound identity, batch number, the structure in Canonical SMILES format, reference to the original source and the EC50 in µM against P. falciparum 3D7 as reported in the ChEMBL-NTD repository.

Data on the 400 Malaria Box compounds 

All compounds in the Malaria Box have been screened in vitro against 3D7 (chloroquine (CQ) sensitive but sulfadoxine resistant strain of P. falciparum) and cytotoxicity assays were performed on human embryonic kidney cell lines (HEK-293). Data are expressed as EC50 in nM for the falciparum data and CC50 in nM, for the cytotoxicity.

The method employed is described by:

- Duffy, S. & Avery, V. M. Development and Optimisation of a Novel Anti-malarial Imaging Assay Validated for High Throughput Screening.  Am. J. Trop. Med. Hyg. 2012, 86, 84-92. DOI: 10.4269/ajtmh.2012.11-0302

IMPORTANT NOTICE: PLATE MAPPING - There are several mappings so only use the one received by email from our compound management partner, at the time of shipping.  Please contact us if you have concerns or need a copy of the plate mapping corresponding to the Malaria Box that was shipped to you.

The list of the 400 compounds in the Open Access Malaria Box (Excel file) contains the information pertaining to each compound.

Important Information

MMV have attempted to include attractive starting points for drug discovery programmes for incorporation in the drug-like set.

However, access to commercially available material in sufficient scale and in a relevant time frame was a major challenge. Consequently a pragmatic approach regarding chemical quality and diversity was taken to achieve an acceptable compromise of activity against P. falciparum and chemical diversity.

Computational and non-computational tools used to elect a compound in the “Drug-like” set.

Both the REOS (Rapid Elimination Of Swill) filters and the PAINS (Pan Assay Interference Compounds) filters were used.

Designing Screens: How to Make your Hits as Hit, Walters, W. P. and Namchuk, M. Nature Reviews Drug Discovery20032, 259 DOI:10.1038/nrd1063

New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays, Baell, J. B. Holloway, G. A.  J. Med. Chem. 201053, 2719–2740 DOI:  10.1021/jm901137j

In the present work any compound from the ChEMBL-NTD dataset that contained one, or more, of these filters was eliminated from consideration.

Also AlogP calculations were based on Ghose-Crippen atom assignments.

- Viswanadhan, V.N., Ghose, A.K.,  Revankar, G.R. & Robins, R.K. J. Chem. Inf. Comput. Sci198929,163. DOI: 10.1021/ci00063a006

Final inclusion/ exclusion of compounds for enhancing the chemical diversity (from those that were active and available) was reviewed through the “wisdom of crowds” methodology via tapping into the collective experience of MMV medicinal chemists.

Library Enhancement through the Wisdom of Crowds, Hack, M. D.; , Rassokhin, D. N.;  Buyck, C.; Seierstad, M.; Skalkin, A.;  Holte, P.;  Jones,T. K.; Mirzadegan, T.;  Agrafiotis, D. Q. J. Chem. Inf. Model. 201151, 3275. DOI: 10.1021/ci200446y

It is also important to note that whilst the activity reported accurately represents the data obtained in the said assays and, furthermore, the quality of each compound has been assessed, it is recommended that any active compound from a screen is re-synthesized/re-purified and retested to confirm that the activity truly resides with the stated structure and not a small percentage of an impurity.

Follow-up guidelines

For suggestions to assess the quality of a hit from the Malaria Box go to the follow-up guidelines.