In silico analysis of tubulin self-assembly inhibition and pharmaceutical profiling of novel vinca alkaloid derivatives

Vinblastine was the first vinca alkaloid (VA) with antiproliferative properties discovered in the plant C. roseus. This study investigates the physicochemical and pharmacological properties of novel vinca derivatives, VADRPA01 and VADRPH01, compared to established vinca alkaloid drugs, including vincristine, vinblastine, vindesine, vinflunine, vinfosiltine, and vinorelbine. This study employs molecular docking and molecular dynamics simulations to investigate the inhibition of tubulin (PDB ID: 5J2T) self-assembly, with a focus on binding affinities and interaction profiles. Results indicate that vincristine, a first-generation alkaloid, exhibits the lowest binding affinity (-6.8 kcal/mol), associated with higher toxicity, while second- (vindesine, -7.4 kcal/mol) and third-generation (vinflunine, -11.1 kcal/mol) drugs demonstrate enhanced affinities. Key interactions, including hydrogen bonds, pi-pi, pi-alkyl, and pi-sigma bonds, were identified, with vinblastine forming robust hydrogen bonds with C:ASN329 and C:LYS336 (-10.8 kcal/mol) and vinorelbine engaging B:LYS176 and C:PHE351 (-10.7 kcal/mol). VADRPA01, a vinblastine derivative, exhibited superior binding affinity (-11.7 kcal/mol) and solubility (LogS7.4 -0.91), forming consistent hydrogen bonds with B:TYR210, C:ASN329, B:VAL177, and B:ASP179, with occupancy rates of 42.31% and 21.15% for B:TYR210 and C:VAL177/C:PHE351, respectively. Conversely, VADRPH01 lacked interaction with C:LYS326. Structural modifications, particularly in dihydrocatheranthine and N-formylvindoline moieties, significantly influenced docking conformations. The integration of docking, molecular dynamics, and gmxMMPB(GB)SA analyses underscores VADRPA01’s enhanced binding stability, positioning it as a promising antimitotic agent. These findings advocate for further development of VADRPA01, highlighting its potential in designing next-generation vinca alkaloids with improved therapeutic efficacy and safety profiles.