Computational insights into the anti-Alzheimer potential of alkynyl-3-carboxamide derivatives.

Alzheimer's disease (AD) remains a major global health challenge due to its complex pathological mechanisms and the limited availability of effective disease-modifying therapies. In this study, a dataset of fifty novel alkynyl-3-carboxamide derivatives (1-50) was systematically evaluated as potential inhibitors of asparagine endopeptidase (legumain), a key enzyme implicated in AD-associated neurodegeneration. An integrated computational approach involving molecular docking, molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy analysis, density functional theory (DFT) calculations, and ADMET profiling was employed to investigate ligand-protein interactions, structural stability, electronic properties, and drug-likeness. Molecular docking analysis across ten disease-relevant protein targets identified ligand 4 as the most promising candidate, showing the highest binding affinity toward legumain (PDB ID: 5LUA) with a docking score of -8.1 kcal mol-1. Temperature-dependent MD simulations performed at 300, 305, 310, and 320 K confirmed the stability of the 5LUA-ligand 4 complex, as indicated by consistently low root-mean-square deviation (RMSD) fluctuations and stable binding interactions. MM/PBSA calculations further demonstrated favorable binding thermodynamics for ligand 4, with a total Gibbs free energy of binding (ΔG_bind) of -37.05 kcal mol-1. Furthermore, physicochemical and pharmacokinetic assessments revealed favorable drug-like characteristics, including compliance with Lipinski's and Veber's criteria, suitable lipophilicity (c log P = 2.03), topological polar surface area (TPSA = 131.4 Å2), and an acceptable predicted hERG inhibition profile (pIC50 = 0.9881) with no significant toxicity alerts. Overall, these computational findings, supported by previously reported in vitro evidence, suggest that ligand 4 represents a promising alkynyl-3-carboxamide-based lead scaffold for further development as a potential legumain-targeted therapeutic candidate for AD. Additional experimental validation through advanced biological assays and in vivo studies is required to confirm its efficacy and safety profile.