Esterified Indole-3-propionicAcid: A Novel Inhibitoragainst Cholinesterase Identified through Experimental and ComputationalApproaches

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are targeted for designing drugs against cognitive dysfunction. Curcumin (CUR) and indole-3-propionic acid (IPA) are known for their neuroprotective activity. The clinical application of CUR is hindered due to poor absorption and bioavailability. Hence, CUR was conjugated with IPA to form the CUR-IPA diester. CUR-IPA inhibition against electric eel AChE (eAChE), human AChE (hAChE), and hBChE was carried out. In silico and molecular dynamics (MD) analyses of the interaction of CUR-IPA with hAChE and hBChE were done. UV–visible spectroscopy (λ_max at 415 and 276 nm), NMR spectrum, and ESI/MS/MS [<i>m</i>/<i>z</i> = 711 (M + H)] confirmed CUR-IPA formation. CUR-IPA showed in vitro antioxidant activity. The IC₅₀ values of eAChE, hAChE, and hBChE enzyme inhibition were 5.66, 59.30, and 60.66 μM, respectively. MD simulation-based analysis such as RMSD, RMSF, free-energy calculation, PCA, FEL, and DCCM confirmed the stable binding of CUR-IPA with hAChE and hBChE. Further QM/MM analysis confirmed the stable interaction of CUR-IPA with hAChE and hBChE. Since CUR-IPA showed in vitro inhibition against AChE and BChE, a further neuroprotective effect in in vivo could be studied.