Virtual Screening and the In Vitro Assessment of the Antileishmanial Activity of Lignans

Abstract

Leishmaniasis is endemic in at least 98 countries. Due to the high toxicity and resistance associated with the drugs, we chose lignans as an alternative, due to their favorable properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET). To investigate their leishmanicidal potential, the biological activities of a set of 160 lignans were predicted using predictive models that were built using data for Leishmania major and L. (Viannia) braziliensis. A combined analysis, based on ligand and structure, and several other computational approaches were used. The results showed that the combined analysis was able to select 11 lignans with potential activity against L. major and 21 lignans against L. braziliensis, with multitargeting effects and low or no toxicity. Of these compounds, four were isolated from the species Justicia aequilabris (Nees) Lindau. All of the identified compounds were able to inhibit the growth of L. braziliensis promastigotes, with the most active compound, (159) epipinoresinol-4-O-β-d-glucopyranoside, presenting an IC50 value of 5.39 µM and IC50 value of 36.51 µM for L. major. Our findings indicated the potential of computer-aided drug design and development and demonstrated that lignans represent promising prototype compounds for the development of multitarget drugs against leishmaniasis.

Use of Natural Products in Leishmaniasis Chemotherapy: An Overview

“…After all these virtual screenings, four lignans (secoisolariciresinol, pinoresinol-4-O-β-D -glucopyranoside, epipinoresinol-4-O-β-D -glucopyranoside, and pinoresinol-4-Oβ-d-apiofuranosyl-(1→2)-β-d-glucopyranoside) were selected, and their potential to inhibit the growth of promastigote forms of L. major and L. braziliensis was tested. Epipinoresinol-4-Oβ-d-glucopyranoside was the only compound that exhibited activity against both species tested, presenting IC 50 values for L. major and L. braziliensis of 36.5 and 5.4 µM, respectively (Maia et al, 2020).…”

“…The diversity in this class consists of the distribution of aromatic rings and the nature of the propyl fragments (Rye and Barker, 2013). Several groups have chosen to investigate lignans and neolignans because they have properties favorable to drug development and for their antiinflammatory and antioxidant activity, which may minimize the effects of the inflammatory response (Maia et al, 2020).…”

“…To optimize the choice of lignans and neolignans with potential effects against Leishmnia species and to prevent possible failures from being detected only in preclinical tests, several computational tools can contribute strongly to database creation by predicting protein functions, modeling protein structures, simulating metabolic pathway kinetics, predicting biological activities, predicting toxicity, and predicting the affinities and flexibilities between receptors and ligands, which can facilitate the development and identification of drugs with the potential to treat various diseases and promote the development of efficacious drugs with reduced toxicity (Maia et al, 2020). The design and synthesis of analogs of natural compounds is a strategy extensively used to identify effective new treatments against leishmaniasis.…”

“…Virtual screening and experimental validation have been utilized to identify lignans with leishmanicidal potential, low toxicity, and selective activity against several Leishmania targets. A set of 160 lignans (i.e., 14 furans, 10 furofurans, 14 dibenzylbutyrolactols, 22 dibenzylbutanes, 21 dibenzocycloocyadienes, 17 aryltetralins, 3 arylnaphthalenes, 8 neolignan alkyl aryl ethers, 16 neolignan benzofurans, and 9 neolignan benzodiones) were selected using predictive models that were built using data for L. major and L. braziliensis (Maia et al, 2020).…”

Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

“…However, virtual screening appears ever more efficient with the development of methodological tools [140,144], but several potential biases were reported [145]. For this reason, although this approach is very interesting, fast, and a cost-efficient alternative to high-throughput screening, the results should be tested and validated experimentally [146][147][148] afterward. Among the most recently published works are those of Khatoon et al [148], which identified original coumarin-isatin hybrids derivatives with antileishmanial activity.…”