In the present study, five known γ‐lactones (majoranolide B – 1, majorenolide – 2, majorynolide – 3, lincomolide D – 4, and isolinderanolide E – 5), as well as a new one (perseanolide – 6), were isolated from Persea fulva and P. americana. All isolated compounds exhibited potential activity against trypomastigote forms of Trypanosoma cruzi, whereas compounds 2 (EC50 of 4.8 μM) and 6 (EC50 of 3.6 μM) displayed superior activity than the positive control benznidazole (EC50 of 16.4 μM), with selectivity index (SI) values of 17.8 and >55.6, respectively (benznidazole, SI>12.2). Molecular docking studies were performed for 1–6 against six T. cruzi molecular targets. Using this approach, we observed that, even though perseanolide (6) showed favorable docking to several studied targets, the results were especially promising for hypoxanthine phosphoribosyl transferase (PDB 1TC1). As PDB 1TC1 is associated to the transference of a monophosphorylated ribose from phosphoribosylpyrophosphate (PRPP) in the ribonucleotide synthesis pathway, this interaction may affect the survival of T. cruzi in mammalian cells. The data herein also indicate that possible intermolecular interactions between 6 and PDB 1TC1 derive from (i) hydrogen bonds in the α,β‐unsaturated‐γ‐lactone unity and (ii) hydrophobic interactions in the long‐chain alkyl group. Based on our results, perseanolide (6), reported for the first time in this work, can auspiciously contribute to future works regarding new trypanocidal agents.
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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