Mechanistic Insights into (3+2) Cycloaddition of Glutaraldehyde-N-Aryl Nitrone with Cinnamaldehyde: Electron Density, Docking, and Molecular Dynamics Analysis

This research provides a thorough computational analysis of the [3 + 2] cycloaddition (32CA) reaction involving Glutaraldehyde-N-aryl nitrone ( GN-1 ) with Cinnamaldehyde ( CA-2 ), utilizing Molecular Electron Density Theory (MEDT) as the interpretive framework. However, the potential energy surface analysis identified four stereoisomeric pathways, with the ortho - endo channel becoming thermodynamically and kinetically better. However, Global Electron Density Transfer (GEDT) values at the transition states (TSs) showed a clear forward electron density flux (FEDF), confirming the polar nature of the main mechanism. Electron Localization Function (ELF) with Bonding Evolution Theory (BET) analyses highlighted asynchronous bond formation along the preferred pathway. The stability of the cycloadducts was further assessed through molecular docking against the EGFR L858R mutant (PDB ID: 2ITZ), where compound IC-6 exhibited the strongest binding affinity. Molecular dynamics (MD) simulations of the IC-6 /EGFR complex over 100 ns validated its stable interaction profile and dynamic conformational behavior within the binding site. Furthermore, Absorption, Distribution, Metabolism, Excretion, with Toxicity (ADMET) predictions confirmed favorable drug-likeness with pharmacokinetic characteristics for synthesized compounds. Overall, integration of GEDT, FEDF, and MD provides deep mechanistic insights into the reaction pathway, while highlighting the therapeutic potential of the resulting isoxazolidine derivatives.