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Matthew Berriman

Avril Coghlan

Prudence Mutowo

Noel O'Boyle

Jane Lomax

Andrew R. Leach

Figure 1

Creating a screening set of potential anthelmintic compounds using ChEMBL

Many existing anthelmintic compounds are compromised by low efficacy, serious side-effects and/or rising resistance in parasite populations. Thus, to reveal potential new anthelmintic drug targets and drugs, we describe a protocol to identify the most promising nematode/flatworm targets, and compounds likely to interact with them from the ChEMBL database \(Gaulton _et al._ 2017), includes both targets of known drugs and of other biologically active compounds. Thus, this provides a potential screening set of drug-like compounds that can be tested for anthelmintic activity.





Our protocol \(Figure 1) starts by using predicted proteins from nematode and platyhelminth genomes to search using BLASTP \(E ≤ 1e-10) \(Altschul _et al._ 1997) against single-protein targets from ChEMBL. To remove redundant hits, the nematode and platyhelminth proteins with significant BLAST hits are collapsed by gene family using an in-house database of gene families \(e.g. built the Ensembl Compara pipeline; Vilella _et al._ 2009). Then, a ‘target score’ is calculated for each worm gene, taking into account similarity to known drug targets; lack of human homologues; and whether _C. elegans_ and _D. melanogaster_ homologues have lethal phenotypes, amongst other factors.





<a href="https://www.nature.com/protocolexchange/system/uploads/6593/original/Figure1.gif?1523716990"><img src="https://www.nature.com/protocolexchange/system/uploads/6593/original/Figure1.gif?1523716990"></a>





**Figure 1. Flowchart of the methods used for identifying potential new anthelmintic targets and drugs using ChEMBL.** The following images were used from Openclipart: ‘prescription-bottle-and-pills’ \(by algotruneman), ‘famous-and-infamous-molecules-13’ \(by Firkin) and ‘worm-gusano’ \(by ainara14).





Next, ChEMBL is used to identify hundreds of thousands of compounds with activities against ChEMBL targets to which worm proteins had BLAST matches. To calculate ‘compound scores’ for those compounds, we prioritise compounds in high clinical development phases, oral/topical administration, crystal structures, properties consistent with oral drugs, and lacking toxicity. At this stage, we focus on the compounds for the top 15% of highest-scoring worm targets, as these are the most promising novel targets. The set of compounds is filtered by selecting compounds that co-appear in a PDBe \(Velankar _et al._) structure with the ChEMBL target; or have high median pChEMBL score, reflecting high potency/affinity for the ChEMBL target. 





Lastly, the candidates are placed into chemical classes, based on molecular fingerprints. Then they are further filtered by \(i) checking availability for purchase in ZINC 15 \(Sterling _et al._ 2015); and \(ii) for each worm target, taking the highest-scoring compound from each chemical class.





This gives a relatively small diverse screening set of a few thousand compounds.





Many previous analyses of nematode and platyhelminth genomes have identified potential novel drug targets among their predicted proteins, and prioritised these based on factors such as lethal knockout phenotypes. However, relatively few previous studies have identified compounds predicted to target those nematode/platyhelminth proteins, and those that have done so \(e.g. Berriman _et al._ 2009) have generally been limited to small numbers of compounds. By analysing the huge wealth of data in the ChEMBL database, this protocol produces much larger sets of compounds to screen for anthelmintic activity.

<a href="https://www.ebi.ac.uk/chembl">ChEMBL database website</a>





<a href="http://www.ebi.ac.uk/pdbe/">PDBe database website</a>





<a href="http://zinc15.docking.org">ZINC15 database website</a>





<a href="https://www.ensembl.org/info/docs/webcode/mirror/index.html">Ensembl Compara pipeline</a>





<a href="http://www.ebi.ac.uk/ena">European Nucleotide Archive website</a>





 <a href="https://www.ebi.ac.uk/arrayexpress">ArrayExpress website</a>





<a href="https://pubchem.ncbi.nlm.nih.gov">PubChem database website</a>





<a href="http://www.genome.jp/kegg/drug">KEGG Drugs database website</a>





<a href="https://www.drugbank.ca">DrugBank database website</a> 





<a href="https://www.ebi.ac.uk/chebi">ChEBI database website</a>





<a href="https://www.wormbase.org">WormBase database website</a>





<a href="http://flybase.org">FlyBase database website</a>

The output from the procedure is a diverse screening set of several thousand compounds from ChEMBL \(including both approved drugs and medicinal chemistry compounds), and their putative targets in nematodes/platyhelminths.

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We would like to thank the WTSI Pathogen Informatics team, especially Jacqueline Keane and Andrew Page.

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Many existing anthelmintic compounds are compromised by low efficacy, serious side-effects and/or rising resistance in parasite populations. Thus, to reveal potential new drug targets and drugs, we describe a protocol to identify the most promising nematode/flatworm targets, and compounds likely to interact with them from the ChEMBL database \(which includes both targets of known drugs and of other biologically active compounds). This provides a potential screening set of drug-like compounds.

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Method Article

Matthew Berriman, Avril Coghlan, Prudence Mutowo, Noel O'Boyle, Jane Lomax, Andrew R. Leach

Matthew Berriman

Berriman Lab Group, Sanger Institute

Corresponding Author

Avril Coghlan

Berriman Lab Group, Sanger Institute

Prudence Mutowo

European Bioinformatics Institute

Noel O'Boyle

NextMove Software

Jane Lomax

Berriman Lab Group, Sanger Institute

Andrew R. Leach

European Bioinformatics Institute

DOI:

10.1038/protex.2018.053

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Abstract

Keywords

drug discovery, drugs, anthemintic, helminths, nematodes, flatworms, parasites, parasitic worms, platyhelminths, Nematoda, Platyhelminthes, compounds, anthelminthic, ChEMBL

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Method Article

Matthew Berriman, Avril Coghlan, Prudence Mutowo, Noel O'Boyle, Jane Lomax, Andrew R. Leach

Matthew Berriman

Berriman Lab Group, Sanger Institute

Corresponding Author

Avril Coghlan

Berriman Lab Group, Sanger Institute

Prudence Mutowo

European Bioinformatics Institute

Noel O'Boyle

NextMove Software

Jane Lomax

Berriman Lab Group, Sanger Institute

Andrew R. Leach

European Bioinformatics Institute

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DOI:

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