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Virtual screening to identify Leishmania braziliensis N-myristoyltransferase inhibitors: pharmacophore models, docking, and molecular dynamics

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Abstract

Leishmaniasis is caused by several protozoa species belonging to genus Leishmania that are hosted by humans and other mammals. Millions of new cases are recorded every year and the drugs available on the market do not show satisfactory efficacy and safety. A hierarchical virtual screening approach based on the pharmacophore model, molecular docking, and molecular dynamics was conducted to identify possible Leishmania braziliensis N-misristoyltransferase (LbNMT) inhibitors. The adopted pharmacophore model had three main features: four hydrophobic centers, four hydrogen-bond acceptor atoms, and one positive nitrogen center. The molecules (n=15,000) were submitted to alignment with the pharmacophore model and only 27 molecules aligned to model. Six molecules were submitted to molecular docking, using receptor PDB ID 5A27. After docking, the ZINC35426134 was a top-ranked molecule (− 64.61 kcal/mol). The molecule ZINC35426134 shows hydrophobic interactions with Phe82, Tyr209, Val370, and Leu391 and hydrogen bonds with Asn159, Tyr318, and Val370. Molecular dynamics simulations were performed with the protein in its APO and HOLO forms for 37 ns in order to assess the stability of the protein–ligand complex. Results showed that the HOLO form was more stable than the APO one, and it suggests that the ZINC35426134 binding stabilizes the enzyme. Therefore, the selected molecule has the potential to meet the herein proposed target.

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Acknowledgements

The authors would like to thank Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB) and Programa de Pós-Graduação em Ciências Farmacêuticas - Universidade Estadual de Feira de Santana-BA.

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Authors and Affiliations

  1. Laboratório de Modelagem Molecular, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil

    Juliana Cecília de Carvalho Gallo, Larissa de Mattos Oliveira, Janay Stefany Carneiro Araújo, Isis Bugia Santana & Manoelito Coelho dos Santos Junior

  2. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil

    Juliana Cecília de Carvalho Gallo, Larissa de Mattos Oliveira, Janay Stefany Carneiro Araújo & Manoelito Coelho dos Santos Junior

  3. Programa de Pós-Graduação em Biotecnologia, Universidade Estadual de Feira de Santana, Feira de Santana, Brazil

    Isis Bugia Santana & Manoelito Coelho dos Santos Junior

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  1. Juliana Cecília de Carvalho Gallo
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  2. Larissa de Mattos Oliveira
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  3. Janay Stefany Carneiro Araújo
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  4. Isis Bugia Santana
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  5. Manoelito Coelho dos Santos Junior
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Correspondence to Juliana Cecília de Carvalho Gallo.

Additional information

This paper belongs to Topical Collection XIX - Brazilian Symposium of Theoretical Chemistry (SBQT2017)

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de Carvalho Gallo, J.C., de Mattos Oliveira, L., Araújo, J.S.C. et al. Virtual screening to identify Leishmania braziliensis N-myristoyltransferase inhibitors: pharmacophore models, docking, and molecular dynamics. J Mol Model 24, 260 (2018). https://doi.org/10.1007/s00894-018-3791-8

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