Quinolone-inspired MCM2-7 helicase inhibitors: Computational design, dynamic stability, and preclinical promise for...

The Mini-Chromosome Maintenance (MCM) 2-7 helicase complex is a pivotal component of the eukaryotic DNA replication machinery and an emerging therapeutic target in oncology due to its role in replication licensing and genomic stability. Despite its biological importance, few small-molecule inhibitors have been rationally developed for this complex, particularly against human MCM2. In this study, we employed a structure-based virtual screening strategy combined with molecular dynamics (MD) simulations, MM-PBSA binding free energy calculations, and comprehensive pharmacokinetic modeling to identify novel quinolone-based inhibitors targeting the AAA⁺ ATPase domain of MCM2. Twelve rationally designed compounds were docked against a refined AlphaFold3-derived structure of human MCM2. Ligands 1, 7, and 8 exhibited the strongest binding affinities (up to -8.66 kcal/mol), outperforming the reference compound ciprofloxacin. MD simulations over 100 ns revealed that Ligand 8 most effectively stabilized the OB-fold and ATPase domains, while Ligand 1 formed a highly persistent hydrogen bond network (mean 7.2 ± 1.8 bonds). MM-PBSA energy decomposition showed Ligand 1 possessed the most favorable binding free energy (-51.27 ± 8.46 kJ/mol), attributed to strong polar solvation contributions. In silico ADMET predictions confirmed low mutagenic risk, extended half-life (≥3h), and favorable drug-likeness, although oral bioavailability remained limited. Collectively, this work establishes a robust computational pipeline for helicase-targeted drug design and identifies promising MCM2 inhibitors with superior binding and pharmacological properties, offering mechanistic insight into ligand-induced stabilization of replication machinery and supporting further in vitro and in vivo exploration as anticancer therapeutics that exploit replication stress vulnerabilities.