Hesperetin as a Potential Adjunctive Antimalarial Candidate: An In Silico Pharmacokinetic and Multi-Target Analysis
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Abstract
Antimalarial drug resistance poses a critical challenge to global malaria control, prompting the exploration of phytochemical-based therapeutic alternatives. Hesperetin, a naturally occurring flavanone with diverse pharmacological activities, has emerged as
a promising antiplasmodial candidate. This study aimed to comprehensively evaluate the pharmacokinetic properties and molecular targets of hesperetin, and to investigate its therapeutic potential against malaria-related pathological conditions via disease enrichment analysis. Pharmacokinetic properties were assessed using Molsoft DL, SwissADME, and ProTox 3.0. Potential protein targets were predicted via three databases: SEA, SwissTargetPrediction, and SuperPRED, with targets identified by two or more databases retained for further analysis. Disease enrichment analysis was subsequently performed using the consolidated target list. Hesperetin demonstrated favourable drug-likeness (DL = 0.59), moderate lipophilicity (LogP= 1.91), acceptable oral bioavailability (F = 0.55), and inactive mutagenicity. Thirteen targets were identified by at least two databases, with CA12, CA4, CA7, and CYP1B1 consistently predicted across all three. Among targets identified by two or more databases, SERPINE1, XDH, and CYP19A1 were directly linked to severe malaria pathology. Disease enrichment analysis identified hypercholesterolaemia as the most significantly associated condition(Log10(P) = -5.9), reflecting the critical role of cholesterol homeostasis in Plasmodium falciparum blood-stage development. The present findings indicate that hesperetin exhibits favourable pharmacokinetic properties suitable for oral administration and a multi-target profile mechanistically aligned with Plasmodium falciparum malaria pathogenesis. These attributes support its potential as a promising adjunctive therapeutic candidate, pending in vivo validation and comprehensive toxicity assessment.
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