Therapeutic potential of Psidium guajava leaf phytochemicals against hepatic encephalopathy: A target-specific drug discovery approach

Abstract

Psidium guajava L., leaves have long been valued in traditional medicine, including hepatoprotective effects with a rich phytochemical composition responsible for diverse. However, their target-specific therapeutic potential against hepatic encephalopathy (HE) remains underexplored. HE is a serious neuropsychiatric disorder resulting from the accumulation of neurotoxins, particularly ammonia, due to impaired liver detoxification. In this study, we adopted an integrative computational approach to explore the therapeutic efficacy of P. guajava leaf-derived phytochemicals against three key HE-related protein targets identified via the GeneCards database: sodium channel protein type 1 subunit alpha/SCN1A (PDB ID: 6AGF), glycine decarboxylase/GLDC (PDB ID: 6I33), and potassium voltage-gated channel subfamily Q member 2/KCNQ2 (PDB ID: 8X43). A total of 89 phytochemicals, along with three standard drugs' binding efficacy were validated through molecular docking using PyRx 0.8-AutoDock 4.2 software, where several phytocompounds demonstrated stronger binding affinities than standard drugs. Further physicochemical, toxicity, pharmacokinetic, and drug-likeness studies were predicted, where PG_LP21 (guaijaverin) and PG_LP75 (rutin) were selected as two lead compounds with favorable drug-likeness profiles. Further, the lead compounds (PG_LP75/rutin) along with their standard drug (SD1/carbamazepine) stability and reactivity were investigated through molecular dynamics (MD) simulations at 100 nanoseconds, and free energy calculation (MM/PBSA) along with HOMO–LUMO analysis supported that PG_LP75 has higher stability. Overall, this study highlights a novel target-specific computational strategy linking traditional herbal knowledge with modern drug discovery, offering promising leads for HE therapeutics from P. guajava.