Molecular Docking and Binding Mode Analysis of Plant Alkaloids as in Vitro and in silico Inhibitors of Trypanothione Reductase from Trypanosoma cruzi

Abstract

Trypanothione reductase (TryR) is a key enzyme in the metabolism of Trypanosoma cruzi, the parasite responsible for Chagas disease. The available repertoire of TryR inhibitors relies heavily on synthetic substrates of limited structural diversity, and less on plant-derived natural products. In this study, a molecular docking procedure using a Lamarckian Genetic Algorithm was implemented to examine the protein-ligand binding interactions of strong in vitro inhibitors for which no X-ray data is available. In addition, a small, skeletally diverse, set of natural alkaloids was assessed computationally against T. cruzi TryR in search of new scaffolds for lead development. The preferential binding mode (low number of clusters, high cluster population), together with the deduced binding interactions were used to discriminate among the virtual inhibitors. This study confirms the prior in vitro data and proposes quebrachamine, cephalotaxine, cryptolepine, (22S,25S)-tomatidine, (22R,25S)-solanidine, and (22R,25R)-solasodine as new alkaloid scaffold leads in the search for more potent and selective TryR inhibitors.

Alkaloids in Contemporary Drug Discovery to Meet Global Disease Needs

“…Alternatively, the active site can be assessed through a combination of in silico and in vitro approaches. Although there have been many in silico studies for anticancer compounds and Alzheimer's derivatives, relatively few studies have examined alkaloids for potential antimicrobial activity, or activity against NTDs or other tropical diseases [164][165][166][167][168].…”

“…One study sought inhibitors of trypanothione reductase, which is important for the proliferation of Chagas' disease, and was initiated with twelve structurally diverse alkaloids bearing a conformational semblance to the trypanothione [165]. Of the twelve alkaloids chosen for in silico binding analysis, and considering the desire for sustainable sourcing, steroidal alkaloids from commercial Solanum species were selected for further in silico structure development, semi-synthesis, and biological assessment.…”

An Overview on Target-Based Drug Design against Kinetoplastid Protozoan Infections: Human African Trypanosomiasis, Chagas Disease and Leishmaniases

“…Derivative 21 and 22 presented higher values of lysis on both strains of T. cruzi than Nfx and Bzn [ 73 ]. In silico studies of Arguelles et al proposed quebrachamine ( 24 ), cephalotaxine ( 25 ), cryptolepine ( 26 ), (22S,25S)-tomatidine, (22R,25S)-solanidine, and (22R,25R)-solasodine as novel alkaloid scaffolds for the development of novel and potent TR inhibitors [ 77 ].…”

Natural Products, the Fourth Industrial Revolution, and the Quintuple Helix

“…Beyond the identification of neglected diseases and the correlation with ethnomedical uses of plants, interwoven with the in silico structures of known and new metabolites with a "fit" to inhibit an active site at an enzyme, there is an opportunity for drug discovery where resources can be focused on a highly select group of compounds whose probability for biological success is enhanced. 56 Acquisition resources are conserved, in vitro testing is limited, and potential toxicities are constrained; it represents a classical ecopharmacognosy outcome.…”