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Structural characterization, biochemical, inhibition and computational studies of Entamoeba histolytica phosphoglycerate mutase: finding hits for a new antiamoebic drug

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Abstract

Entamoeba histolytica is the causative agent of amoebiasis, which infects an estimated 50 million people globally each year. This parasite uses glycolysis as its only source of energy making enzymes of this route such as phosphoglycerate mutase (EhPGAM) excellent targets in the search for new drugs, a continuing necessity due to the adverse effects and unsuccessful cases of treatment that have resulted from the use of available antiparasitic agents. The aim of this work is to present the biochemical and structural characterization of EhPGAM and the results of a search for the first inhibitors of this enzyme. To this end, the activity of purified recombinant EhPGAM was assessed against an in-house chemical library of 200 benzimidazole derivatives. The results showed that seven compounds inhibited this enzyme about 40–70% at 100 μM and molecular dynamics simulations indicated that the two most potent inhibitors (Compound 1 and Compound 2) form stable complexes and have the highest binding energy. Hence, these inhibitors can be considered good candidates in the search of new drugs to treat amoebiasis.

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Acknowledgements

The authors acknowledge DGESCA for the use of supercomputer Miztli. ATV and CAD acknowledge CONACyT for grants No. 257848 and No. 258694, respectively. CONACyT is also acknowledged by ALC (fellowship No. 231153) and EESC (fellowship No. 283595).

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Authors and Affiliations

  1. Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango Av. Universidad y Fanny Anitúa S/N, Durango, CP 34000, Mexico

    Artemisa Luévano-De la Cruz, Claudia Avitia-Domínguez & Alfredo Téllez-Valencia

  2. Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, Ciudad de México, CP 04510, Mexico

    Elkin Eduardo Sanabria-Chanaga, Rafael Castillo & Alicia Hernández-Campos

  3. IMSS, Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Ciudad de México, CP 06720, Mexico

    Lilián Yépez-Mulia

  4. Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana, Unidad Cuajimalpa Av. Vasco de Quiroga 4871, Colonia Santa Fe Cuajimalpa, Delegación Cuajimalpa de Morelos, Ciudad de México, CP 05300, Mexico

    Hugo Nájera

  5. Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Artículo 123S/N Fracc. Filadelfia, Gómez Palacio, Durango, CP 35010, Mexico

    Erick Sierra-Campos & Mónica Valdez-Solana

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  1. Artemisa Luévano-De la Cruz
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  2. Elkin Eduardo Sanabria-Chanaga
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  6. Hugo Nájera
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  10. Alfredo Téllez-Valencia
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Correspondence to Alfredo Téllez-Valencia.

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la Cruz, A.LD., Sanabria-Chanaga, E.E., Yépez-Mulia, L. et al. Structural characterization, biochemical, inhibition and computational studies of Entamoeba histolytica phosphoglycerate mutase: finding hits for a new antiamoebic drug. Med Chem Res 27, 1705–1716 (2018). https://doi.org/10.1007/s00044-018-2184-y

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