Novel atorvastatin-curcumin conjugate nanogel, a selective COX2 inhibitor with enhanced biopharmaceutical profile: Design, synthesis, in silico, in vitro, and in vivo investigation

In the current research, the main attention was to overcome solubility related issues of atorvastatin (AC), and curcumin (CUR) through atorvastatin-curcumin conjugate (AC-CUR) synthesis and access its synergistic action on inflammation. The nanocrystals of AC, CUR, and AC-CUR were prepared and produced nanocrystals were incorporated into the aqueous and emul gel formulations followed by further in vivo characterization. The synergistic effect of the AC-CUR conjugate was established before conjugate synthesis using in-silico analysis. The protein structure was confirmed by the Ramachandran plot, and docking with COX 1 (PDB ID: 3N8Y) and COX 2 (PDB ID: 1CX2) revealed significant affinities of -10.5 kcal/mol and -13.24 kcal/mol, respectively. Subsequently, the stability in the biological system was examined using molecular dynamic simulation. Numerous analyses confirmed the successful synthesis of the conjugate, and the solubility was found to increase by similar to 2 folds. The zeta potential of the nanocrystals was found -35mv which signified the excellent stability of the nanocrystals. The scanning electron microscopy (SEM) image confirmed the spherical morphology of the prepared nanocrystals. The particle size of the nanocrystal was found between 25 and 450 nm, and the drug release was observed up to 28 h using nano gel formulations. The appropriate nano gel formulations were chosen for in vivo testing using mice inflammatory model. The new conjugate molecule revealed excellent biopharmaceutical properties and improved anti-inflammatory efficacy, therefore AC-CUR nanogel could be an efficient and smart platform in the treatment of inflammation.