Ural_2026_J.Comput.Aided.Mol.Des_40_

In this study, coumarin-3-carboxamide derivatives were designed and evaluated through a comprehensive in silico and in vitro combined approaches to identify cholinesterase inhibitors. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA analyses revealed strong binding affinities and stable interactions within key catalytic regions of AChE and BChE, with AChE-CM4 (deltaG(bind) = -60.27 +/- 5.88 kcal/mol) and BChE-CM5 (deltaG(bind) = -54.95 +/- 6.90 kcal/mol) emerging as the most promising complexes. ADME predictions indicated generally favorable pharmacokinetic profiles for the compounds; however, the predicted blood-brain barrier permeability levels were low to moderate. In vitro enzyme inhibition studies validated the computational results, showing that CM4 (IC(50) = 19.04 +/- 1.67 nM) and CM8 (IC(50) = 17.73 +/- 0.66 nM) exhibited significantly greater AChE inhibition than donepezil (IC(50) = 27.27 +/- 1.22 nM; p < 0.001), with CM3 (IC(50) = 24.84 +/- 1.99 nM) comparable to donepezil, while all derivatives (CM1-CM9) significantly outperformed tacrine against BChE (p < 0.001). Moreover, CM6 and CM9 inhibited colony formation in brain, breast, and colon cancer cell lines at concentrations below 5 microM. As a result, the alignment of computational and biological data highlights these coumarin-3-carboxamides as compelling lead candidates with both neuroprotective and anticancer potential for further pharmacological development.