Molecular Modelling Study of Heteroarylamide/Sulfonamide Compounds with Antitrypanosomal Activity

Souza, André L. P. F.; Cardoso, Fábio José Bonfim; Martins, Lucas Sousa; Alves, Cláudio Nahum; Silva, José R. A.; Molfetta, Fábio Alberto de

doi:10.21577/0103-5053.20200158

Cited by 4 publications

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“…The binding affinity between the studied compound and the macromolecule was determined by calculating the binding free energy, which is an important tool for designing potent enzymatic inhibitors [ 77 ]. The amino acids Cys52, Gly326, Asp327, Leu334, and Thr335 contributed to the stabilization of the (-)-5-demethoxygrandisin B ligand in the complex.…”

Section: Discussionmentioning

confidence: 99%

(-)-5-Demethoxygrandisin B a New Lignan from Virola surinamensis (Rol.) Warb. Leaves: Evaluation of the Leishmanicidal Activity by In Vitro and In Silico Approaches

Paes,

Silva-Silva,

Portal Gomes

et al. 2023

Pharmaceutics

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Leishmaniasis is a complex disease caused by infection with different Leishmania parasites. The number of medications used for its treatment is still limited and the discovery of new drugs is a valuable approach. In this context, here we describe the in vitro leishmanicidal activity and the in silico interaction between trypanothione reductase (TryR) and (-)-5-demethoxygrandisin B from the leaves of Virola surinamensis (Rol.) Warb. The compound (-)-5-demethoxygrandisin B was isolated from V. surinamensis leaves, a plant found in the Brazilian Amazon, and it was characterized as (7R,8S,7′R,8′S)-3,4,5,3′,4′-pentamethoxy-7,7′-epoxylignan. In vitro antileishmanial activity was examined against Leishmania amazonensis, covering both promastigote and intracellular amastigote phases. Cytotoxicity and nitrite production were gauged using BALB/c peritoneal macrophages. Moreover, transmission electron microscopy was applied to probe ultrastructural alterations, and flow cytometry assessed the shifts in the mitochondrial membrane potential. In silico methods such as molecular docking and molecular dynamics assessed the interaction between the most stable configuration of (-)-5-demethoxygrandisin B and TryR from L. infantum (PDB ID 2JK6). As a result, the (-)-5-demethoxygrandisin B was active against promastigote (IC50 7.0 µM) and intracellular amastigote (IC50 26.04 µM) forms of L. amazonensis, with acceptable selectivity indexes. (-)-5-demethoxygrandisin B caused ultrastructural changes in promastigotes, including mitochondrial swelling, altered kDNA patterns, vacuoles, vesicular structures, autophagosomes, and enlarged flagellar pockets. It reduced the mitochondria membrane potential and formed bonds with important residues in the TryR enzyme. The molecular dynamics simulations showed stability and favorable interaction with TryR. The compound targets L. amazonensis mitochondria via TryR enzyme inhibition.

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Section: Discussionmentioning

confidence: 99%