ArticleInternational journal for parasitology. Drugs and drug resistance2016
In silico analysis of the binding of anthelmintics to Caenorhabditis elegansP-glycoprotein 1.
Article in International journal for parasitology. Drugs and drug resistance, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.
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Who cites it
20 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.
- A rapid evidence assessment of the potential risk to the environment presented by active ingredients in the UK's most commonly sold companion animal parasiticides.Environmental science and pollution research international · 2022Pooled it
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- Virtual screening, molecular dynamics simulations, andFrontiers in veterinary science · 2025Article
- Genetic polymorphism, constitutive expression and tissue localization of Dirofilaria immitis P-glycoprotein 11: a putative marker of macrocyclic lactone resistance.Parasites & vectors · 2022Article
- Transgenic Expression ofInternational journal of molecular sciences · 2022Article
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- Computer-aided identification of potential inhibitors againstInformatics in medicine unlocked · 2022Article
- Ivermectin: An Anthelmintic, an Insecticide, and Much More.Trends in parasitology · 2021Review
- Reversal of Ovarian Cancer Cell Lines Multidrug Resistance Phenotype by the Association of Apiole with Chemotherapies.Pharmaceuticals (Basel, Switzerland) · 2020Article
- The P-glycoprotein repertoire of the equine parasitic nematode Parascaris univalens.Scientific reports · 2020Article
- The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12.Scientific reports · 2020Article
- Drug resistance in liver flukes.International journal for parasitology. Drugs and drug resistance · 2020Review
- Plant-Derived Compounds as a Tool for the Control of Gastrointestinal Nematodes: Modulation of Abamectin Pharmacological Action by Carvone.Frontiers in veterinary science · 2020Article
- Emodepside has sex-dependent immobilizing effects on adult Brugia malayi due to a differentially spliced binding pocket in the RCK1 region of the SLO-1 K channel.PLoS pathogens · 2019Article
- Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance.International journal for parasitology. Drugs and drug resistance · 2019Review
- Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13.International journal for parasitology. Drugs and drug resistance · 2018Article
- P-glycoproteins play a role in ivermectin resistance in cyathostomins.International journal for parasitology. Drugs and drug resistance · 2017Article
- Comparison of constitutive and thiabendazole-induced expression of five cytochrome P450 genes in fourth-stage larvae of Haemonchus contortus isolates with different drug susceptibility identifies one gene with high constitutive expression in a multi-resistant isolate.International journal for parasitology. Drugs and drug resistance · 2017Article
- Polymorphism in ABC transporter genes of Dirofilaria immitis.International journal for parasitology. Drugs and drug resistance · 2017Article
- Anthelmintics: From discovery to resistance II (San Diego, 2016).International journal for parasitology. Drugs and drug resistance · 2016Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Macrocyclic lactones (ML) are important anthelmintics used in animals and humans against parasite nematodes, but their therapeutic success is compromised by the spread of ML resistance. Some ABC transporters, such as p-glycoproteins (Pgps), are selected and overexpressed in ML-resistant nematodes, supporting a role for some drug efflux proteins in ML resistance. However, the role of such proteins in ML transport remains to be clarified at the molecular level. Recently, Caenorhabditis elegans Pgp-1 (Cel-Pgp-1) has been crystallized, and its drug-modulated ATPase function characterized in vitro revealed Cel-Pgp-1 as a multidrug transporter. Using this crystal structure, we have developed an in silico drug docking model in order to study the binding of ML and other anthelmintic drugs to Cel-Pgp-1. All tested ML bound with high affinity in a unique site, within the inner chamber of the protein, supporting that ML may be transported by Cel-Pgp-1. Interestingly, interacting residues delineate a ML specific fingerprint involving H-bonds, including T1028. In particular, benzofurane and spiroketal moieties bound to specific sub-sites. When compared with the aglycone ML, such as moxidectin and ivermectin aglycone, avermectin anthelmintics have significant higher affinity for Cel-Pgp-1, likely due to the sugar substituent(s) that bind to a specific area involving H-bonds at Y771. Triclabendazole, closantel and emodepside bound with good affinities to different sub-sites in the inner chamber, partially overlapping with the ML binding site, suggesting that they could compete for Cel-Pgp-1-mediated ML transport. In conclusion, this work provides novel information on the role of nematode Pgps in transporting anthelmintics, and a valuable tool to predict drug-drug interactions and to rationally design new competitive inhibitors of clinically-relevant nematode Pgps, to improve anthelmintic therapeutics.
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