Computational identification of AKT1-modulating phytochemicals from Moringa oleifera targeting the PI3K/AKT/mTOR...

Protein kinase B (AKT1) plays a critical role in neuronal development, synaptic plasticity, and cognitive function. Dysregulation of AKT1 and its associated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway has been implicated in the pathophysiology of Autism Spectrum Disorder (ASD). However, ASD is a multifactorial disorder involving multiple signaling pathways, and PI3K/AKT/mTOR crosstalk with other neurodevelopmental pathways must also be considered. Moringa oleifera, a medicinal plant rich in bioactive phytochemicals, has attracted attention for its neuroprotective, antioxidant, and anti-inflammatory properties. The present study aims to computationally evaluate the binding potential of selected Moringa oleifera phytochemicals against AKT1 using an integrated in silico approach, thereby exploring their possible modulatory effects at the pathway level rather than direct epigenetic regulation.

Phytochemicals of Moringa oleifera were retrieved from Dr. Duke's Phytochemical and Ethnobotanical Databases. Pharmacokinetic profiling (absorption, distribution, metabolism, and excretion) and toxicity prediction were performed using POM (Petra/Osiris/Molinspiration) analysis. Molecular docking was conducted to evaluate binding affinity and interaction patterns between AKT1 and selected ligands, followed by molecular dynamics (MD) simulations to assess the structural stability of the docked complexes over time.

Among the screened compounds, Niazmin and Brassicasterol exhibited the highest binding affinities with docking scores of -8.9 kcal/mol and -8.8 kcal/mol, respectively. These interactions were stabilized by key hydrogen bonds and hydrophobic interactions within the AKT1 binding pocket. MD simulation analyses demonstrated stable complex formation, with consistent root mean square deviation (RMSD) and limited residue fluctuations (RMSF), supporting the structural integrity of the ligand-protein complexes.

The findings suggest that Niazmin and Brassicasterol may act as potential modulators of the PI3K/AKT/mTOR signaling pathway through stable binding with AKT1. However, no direct epigenetic analysis (e.g., DNA methylation or histone modification prediction) was performed; therefore, conclusions are limited to pathway-level modulation rather than confirmed epigenetic regulation. While the antioxidant and anti-inflammatory properties of these phytochemicals may contribute to neuroprotective effects, the present results are based solely on in silico approaches and do not confirm biological activity. Further in vitro and in vivo studies, along with advanced computational analyses such as MM-PBSA and pathway enrichment, are required to validate their therapeutic potential in ASD.