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

Steven Souza Paes; João Victor Silva-Silva; Paulo Wender Portal Gomes; Luely Oliveira da Silva; Ana Paula Lima da Costa; Manoel Leão Lopes Júnior; Daiana de Jesus Hardoim; Carla J Moragas-Tellis; Noemi Nosomi Taniwaki; Alvaro Luiz Bertho; Fábio Alberto de Molfetta; Fernando Almeida-Souza; Lourivaldo Silva Santos; Kátia da Silva Calabrese

doi:10.3390/pharmaceutics15092292

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

Pharmaceutics. 2023 Sep 7;15(9):2292. doi: 10.3390/pharmaceutics15092292.

Authors

Steven Souza Paes¹, João Victor Silva-Silva^{2

3}, Paulo Wender Portal Gomes⁴, Luely Oliveira da Silva⁵, Ana Paula Lima da Costa¹, Manoel Leão Lopes Júnior¹, Daiana de Jesus Hardoim², Carla J Moragas-Tellis⁶, Noemi Nosomi Taniwaki⁷, Alvaro Luiz Bertho^{8

9}, Fábio Alberto de Molfetta¹⁰, Fernando Almeida-Souza^{2

11}, Lourivaldo Silva Santos¹, Kátia da Silva Calabrese²

Affiliations

¹ Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil.
² Laboratory of Protozoology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21041-250, RJ, Brazil.
³ Laboratory of Medicinal and Computational Chemistry, Institute of Physics of São Carlos, University of São Paulo, São Carlos 13418-900, SP, Brazil.
⁴ Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92123, USA.
⁵ Department of Natural Sciences, Pará State University, Belém 66095-015, PA, Brazil.
⁶ Laboratory of Natural Products for Public Health, Pharmaceutical Technology Institute, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil.
⁷ Electron Microscopy Nucleus, Adolfo Lutz Institute, São Paulo 01246-000, SP, Brazil.
⁸ Laboratory of Immunoparasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil.
⁹ Flow Cytometry Core Facility, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil.
¹⁰ Laboratory of Molecular Modeling, Institute of Exact and Natural Sciences, Federal University of Pará, Belém 66075-110, PA, Brazil.
¹¹ Postgraduate Program in Animal Science, State University of Maranhão, Sao Luis 65055-310, MA, Brazil.

Abstract

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.

Keywords: Leishmania amazonensis; computational studies; flow cytometry; mitochondrial membrane potential; trypanothione reductase.

Abstract

Grants and funding