Network pharmacology and in silico validation of sesamin targeting AR and MAPK1 in COVID-19 and malaria

Abstract

Introduction: COVID-19 and malaria may coexist in endemic regions, creating diagnostic and therapeutic challenges, while evidence-based strategies addressing their co-occurrence remain limited. Objective: This study evaluates sesamin, a natural compound with reported antiviral, antioxidant, anti-inflammatory, and immunomodulatory activities, as a potential multitarget candidate for COVID-19 and malaria. Methods: Network pharmacology and transcriptomic analyses were used to identify shared targets and pathways among sesamin, COVID-19, and malaria. Molecular docking; absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling; 200-ns molecular dynamics simulations; and molecular mechanics/generalized Born surface area (MM-GBSA) binding free-energy calculations were performed to assess target interactions, dynamic stability, binding energetics, and predicted pharmacokinetic and toxicity properties. Results: Seventy common differentially expressed genes were identified. Protein–protein interaction analysis highlighted AR, MAPK1, caspase-3, β-catenin, IL-6, HSP90α, and EGFR as key targets. Enrichment analysis linked the genes of these proteins mainly to apoptosis regulation and to FOXO and PI3K–AKT signaling. Sesamin showed favorable docking with MAPK1, AR, EGFR, CASP3, and β-catenin, with docking scores ranging from −10.0 to −8.6 kcal/mol, more favorable than those of the reference ligands. ADMET analysis indicated a potential Ames toxicity signal but no predicted hepatotoxicity or skin sensitization. During the simulations, sesamin remained stable with AR and MAPK1; the AR-bound system showed greater positional stability and lower solvent exposure, whereas the MAPK1-bound system maintained more hydrogen bonds. MM-GBSA analysis showed favorable binding of sesamin to AR (−55.77 kcal/mol) and MAPK1 (−122.17 kcal/mol). Conclusion: Sesamin may modulate shared immune and inflammatory pathways relevant to COVID-19 and malaria. Its stable interactions with AR and MAPK1 support further investigation, although experimental and clinical validation is required.