Integrated Computational and Analytical Approach to Identify Mitogen‐Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Inhibitors From <i>Leucophyllum frutescens</i> for Alzheimer's Disease

ABSTRACT Leucophyllum frutescens , an evergreen ornamental shrub of much density native to arid areas, mostly southwest Texas and Mexico, is of great interest because of its diverse pharmacological properties. This study aimed to examine the possibility of using flower extracts of L. frutescens as a source of inhibitors of mitogen‐activated protein kinase kinase kinase 4 (MAP3K4) for Alzheimer's disease (AD) therapy using an integrated computational and analytical approach. The methanolic extract of L. frutescens (MELF) was analyzed using liquid chromatography‐mass spectrometry (LC‐MS), which revealed the presence of a variety of phytochemicals, including flavonoids, phenolic acids, terpenoids, and fatty acids. Drug‐likeness and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses showed a number of candidate compounds with favorable physicochemical properties and safety. Molecular docking studies were then performed to screen for the binding affinity and interaction of these compounds with the MAP3K4 active site. The top‐ranked ligand‐protein complexes, including flavonoids such as luteolin (LUT) and fisetin (FIE), along with a known synthetic MAP3K4 inhibitor (CCl) used as a reference, were subjected to molecular dynamics (MD) simulations to estimate their stability for 500 ns. Subsequently, calculations of the binding free energy based on the molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) were performed. Major findings from the research indicated that LUT and FIE are the most promising naturally derived MAP3K4 inhibitors, establishing the best binding affinity and stability characteristics. This multidisciplinary approach combines phytochemistry and computational drug discovery, urging experimental validation and paving the way for future therapeutic development of L. frutescens ‐derived compounds used as potential disease‐modifying agents for AD targeting critical MAP3K4 pathways. These results provide ample justification for further research into compounds sourced from L. frutescens as potential therapeutic interventions against AD. Further in vitro and in vivo studies are warranted to validate the efficacy and safety of these treatments.