Quantum mechanical and molecular dynamics insights into the binding mechanism of tubulin-stabilizing agents at the taxol site of β-tubulin.

CONTEXT: Microtubules, composed of α- and β-tubulin heterodimers, play a crucial role in cell division and are well-established targets for anticancer drugs known as tubulin-binding agents (TBAs). Targeting the Taxol-binding site of β-tubulin has been particularly effective in disrupting microtubule dynamics and inhibiting cancer cell proliferation. In this study, selected TBAs were evaluated to identify potential candidates capable of stabilizing microtubules through interactions at this binding site.

METHODS: An integrated computational strategy combining molecular docking, density functional theory (DFT), and molecular dynamics (MD) simulations was employed to investigate the binding characteristics of TBAs. Initially, 97 compounds were screened using a stringent molecular docking approach. Based on binding affinity and interaction analysis, four compounds (TBA79, TBA80, TBA81, and TBA41) were identified as promising candidates. Interaction profiling assessed hydrogen bonding and hydrophobic interactions with key residues. MD simulations (500 ns each) were conducted to evaluate the stability of the protein-ligand complexes. Furthermore, MMGBSA binding free energy calculations and DFT analyses were performed to examine binding stability, reactivity, and charge transfer properties of the selected compounds.