Title:Structure- and Ligand-Based Approaches to Evaluate Aporphynic Alkaloids from Annonaceae as Multi-Target Agent Against Leishmania donovani
Volume: 22
Issue: 34
Author(s): Vitor Prates Lorenzo, Ana Silvia Suassuna Carneiro Lúcio, Luciana Scotti, Josean Fechine Tavares, José Maria Barbosa Filho, Tatjana Keesen de Souza Lima, Juliana da Câmara Rocha and Marcus Tullius Scotti
Affiliation:
Keywords:
Alkaloids, Anaxagorea dolichocarpa, Virtual Screening, Molecular Docking, Random Forest, Leishmania donovani,
antileishmania activity.
Abstract: Background: Leishmaniasis is a neglected disease that affects 15 million people
around the world. Many limitations are associated to the treatment as high cost and toxicity.
Several classes of natural substances with proven leishmanicidal activity were reported
in the literature. Phytochemsitry study of Anaxagorea dolichocarpa (Annonacea) reported
the isolation of aporphine alkaloids.
Methods: In this study, we evaluate the potential activity of the azaphenanthrene alkaloids
eupolaramine, imbiline 1, imbiline 4, sampangine, 3-metoxisampangine and 4-
metoxisampangine, isolated from A. dolichocarpa, together with a homemade databank of
142 aporphynic alkaloids isolated from Annonaceae, through ligand-based and structurebased
virtual screening (VS) against Leishmania donovani. A diverse set selected from
CHEMBL databank of 1397 structures, with tested antileishmanial activity against promastigote L. donovani,
were classified according pIC50 values in order to generate and validate Random Forest model that show higher
statistical indices values. The structure of six different L. donovani enzymes were downloaded from PDB databank
and alkaloids structures were submitted to molecular docking.
Results: From the six azaphenanthrene alkaloids, sampangine, 3-methoxy, and 4-methoxy were indicated as
potential actives by the RF model. Docking results gave similar values for all six azaphenanthrene alkaloids.
So, we performed in vitro tests with sampangine, imbiline 1, imbiline 4, and eupolaramine, which are available
in our laboratory, and that show significant values of pIC50 (> 5.26).
Conclusion: Combined approach of VS allowed us to select that aporphynic alkaloid xyloguyelline as potential
multitarget compound for leishmanial treatment, presenting activity against five strategic enzymes to treatment
with probability of activity over 60% by RF model.
