Design, Synthesis, and Anticancer Evaluation of a Limonene‐Based <scp>LIM</scp> ‐ <scp> <i>co</i> </scp> ‐ <scp>NCA</scp> Copolymer via Experimental and Computational Approaches

ABSTRACT In this study, a novel copolymer of limonene and N ‐cyclohexylacrylamide (LIM‐ co ‐NCA) was synthesized and extensively characterized for both its physicochemical and biological properties. The chemical structure of the copolymer was confirmed through Fourier transform infrared and proton nuclear magnetic resonance spectroscopic techniques. Gel Permeation Chromatography (GPC) analysis revealed that LIM‐ co ‐NCA possesses low molecular weight and oligomeric characteristics. Thermal stability was evaluated using thermogravimetric analysis, while its antiproliferative potential was assessed against the HeLa cervical cancer cell line, demonstrating inhibitory effects. This study investigates the stability and binding affinities of Comp1, Comp2, and Comp3 ligands with 3FAA and 6GUB receptors using computational chemistry methods. Ligand geometries were optimized by density functional theory, and molecular dynamics simulations of 100 ns were performed with GROMACS to evaluate the conformational stability of ligand–receptor complexes. Binding free energies were calculated using the Molecular Mechanics Poisson–Boltzmann surface area approach, including per–residue decomposition to identify critical stabilizing residues. The results demonstrated a receptor–dependent binding preference: Comp2 achieved the strongest stabilization in 3FAA, supported by balanced electrostatic and hydrophobic interactions, while Comp3 dominated in 6GUB, forming a dense arginine‐rich hydrogen bond network and highly favorable electrostatic interactions. Comp1, with its compact scaffold and limited hydrogen bonding capacity, consistently showed moderate binding strength, performing better in 3FAA than in 6GUB. These findings provide valuable insights into receptor‐specific binding mechanisms and highlight the importance of optimizing both electrostatic and hydrophobic contributions in ligand design.