Abstract
N-myristoyltransferase 1 (NMT-1) catalyzes the co-translational addition of myristic acid to the N-terminal glycine of substrate proteins, regulating membrane localization and protein-protein interactions essential for oncogenic signaling. Its overexpression in diverse malignancies has rendered NMT-1 a valuable target for anticancer drug discovery. The study identified four promising inhibitors (Diverse-lib ID: 17506136, 103050917, 24289547, and 24314423) with docking scores ranging from - 11.5 to - 11.2 kcal/mol. DFT analysis revealed favorable frontier orbital characteristics, particularly in 24,289,547, which exhibited the lowest HOMO-LUMO ΔE(gap) (3.516 eV), supporting its electronic suitability for enzyme binding. Redocking of optimized ligands into the active site of NMT-1 confirmed key interactions with catalytic residues Asp(184), Asp(471), Phe(188), Tyr(296), and His(298). 500-ns molecular dynamics (MD) simulations (in triplicate) demonstrated that compound 24,289,547 consistently retained stable binding, as evidenced by low root-mean-square deviation (RMSD) values, persistent hydrogen bond interactions, and tightly clustered conformations in principal component analysis (PCA). Free energy landscape analysis further highlighted 24,289,547 convergences into a single, deep thermodynamic basin. MM/GBSA binding energy calculations identified 24,289,547 as the most favorable inhibitor (ΔG_total = - 102.72 kcal/mol), exceeding the reference compound. Structural superposition with initially docked poses yielded RMSD < 1.25 Å, indicating conformational fidelity. Collectively, these findings establish 24,289,547 as a leading NMT-1 inhibitor candidate. Its stable interaction with the Asp(184)-Asp(471) catalytic motif and peripheral residues suggests a robust biochemical basis for inhibition, offering significant promise for further optimization and therapeutic application in NMT-1-associated cancers.