Multiscale Computational Study of Interactions Between Novel Quinoline Derivatives and the Colchicine‐Binding Site of Tubulin

Abstract

Tubulin is an important anticancer target, and its colchicine‑binding site has attracted considerable attention due to its ability to disrupt microtubule dynamics. In this study, an integrated computational strategy—combining molecular docking, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations—was employed to investigate six novel quinoline derivatives targeting this site. The results showed that compounds 23 and 24g exhibited the most favorable docking affinities (binding energies of −11.200 and −11.105 kcal/mol, respectively), driven by a synergistic effect of van der Waals interactions, electrostatic forces, and hydrogen‑bond networks. DFT analysis indicated that 24g possesses a large dipole moment (12.503 Debye), which may indicate favorable membrane permeability, while a narrow HOMO–LUMO gap (e.g., 2.21 eV for 25g) may suggest high chemical reactivity. MD simulations indicated that the 23 and 24g complexes display high conformational stability, featuring persistent hydrogen‑bond networks and minimal RMSD fluctuations. Energy decomposition analysis identified Lys254, Asn249, and Gln11 as key residues, with van der Waals interactions dominating the binding (e.g., the van der Waals contribution between 24g and Lys254 reached –17.35 kJ/mol). This work provides atomic‑level insight into the interaction mechanism between quinoline derivatives and tubulin, highlighting 23g/24g as potential candidates for the development of antimitotic agents.