What question did this study set out to answer?

To identify and evaluate xanthone derivatives as potential multi-target therapeutic candidates against Trypanosoma cruzi using an integrated in silico screening pipeline.

August 16, 2026Journal of Pharmaceutical Innovation0 citationsOpen Access

Multi-Target Analysis of Xanthone Derivatives as Potential Anti-Trypanosoma cruzi Agents: An Integrated Computational Screening

RMRafael de Oliveira Marinho CGCaroline do Nascimento Gonçalves JSJacilene Silva

Key Points

To identify and evaluate xanthone derivatives as potential multi-target therapeutic candidates against Trypanosoma cruzi using an integrated in silico screening pipeline.
Screened eight xanthone derivatives using physicochemical, pharmacokinetic, and toxicological filters.
Performed molecular docking and pharmacophoric mapping against T. cruzi targets Tc Reductase and Tc GAPDH.
Assessed dynamic stability and ligand interactions using conformational stability simulations.
Predicted pharmacokinetic parameters showed human intestinal absorption > 90%, apparent permeability > 1.0 × 10⁻⁵ cm/s, and TPSA < 90 Å², indicating high oral bioavailability.
Compounds XN1 and XN5 achieved multi-parameter optimization scores of 5 with molecular weights below 400 g/mol.
Compound XN5 showed superior docking affinity and conformational stability for Tc Reductase and Tc GAPDH compared to co-crystallized reference ligands.

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi , affects approximately 8 million people worldwide. The search for new therapeutic candidates is intensified by the limited efficacy and severe adverse effects of current treatments, such as benznidazole and nifurtimox. In this context, integrated computational strategies encompassing structural, dynamic, and pharmacokinetic filters act complementarily to guide the rational screening of promising compounds. Here, eight xanthone derivatives were evaluated using integrated in silico approaches, including multiparametric analyses of physicochemical, pharmacokinetic, toxicological, molecular docking, and conformational stability properties. Pharmacokinetic predictions indicated high human intestinal absorption (> 90%), apparent permeability consistent with efficient transcellular diffusion (Papp > 1.0 × 10⁻⁵ cm/s), and TPSA values below 90 Å², suggesting favorable oral bioavailability. Among the compounds, XN1 and XN5 emerged as promising candidates, showing multi-parameter optimization (MPO) scores of 5, molecular weights below 400 g/mol, and advantageous absorption and permeability profiles. Although XN5 exhibited higher lipophilicity and associated toxicity alerts, both compounds demonstrated promising pharmacokinetic features. Molecular docking analyses revealed that XN5 presented superior binding affinity for Tc Reductase and Tc GAPDH, outperforming co-crystallized ligands and suggesting stable protein-ligand complexes. Pharmacophoric mapping confirmed the conservation of key molecular recognition features, corroborating the stereoelectronic complementarity of xanthone derivatives with the active sites. conformational stability simulations further indicated that XN5 exhibited the most stable behavior with Tc Reductase and a performance comparable to BZN and chalepin with Tc GAPDH. In conclusion, in silico results highlight XN5 as a promising candidate for Chagas disease treatment.

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