Computational assessment of the reactivity and pharmaceutical potential of novel triazole derivatives: An approach combining DFT calculations, molecular dynamics simulations, and molecular docking

The worldwide prevalence of cancer and its increasing frequency make it a key research area in drug discovery programs. The current research paper describes the development of QSAR models based on the in vitro against topoisomerase II, which identified the structural origin of anticancer activity for derivatives of triazole moieties linked to mansonone E. The models PLS regression QSARs validated by LOO showed an R2 of 0.92, 0.89 and 0.99 and a Q2 of 0.75, 0.62 and 0.88 for CoMFA, CoMSIA and HQSAR respectively. External validation criteria were used to validate the reliability of the models. These results show the impact of electrostatic and steric fields and of the hydrogen bond donor on the activity of the compounds studied. Based on these results, seven novel inhibitors with high activity were designed, which successfully passed Lipinski's rule of five for oral bioavailability. The evaluations of ADME/Tox parameters and synthetic accessibility for chemical synthesis showed acceptable results. Ligand interactions in binding site protein were assessed using molecular docking. The results show the correct conformational pose of the designed compounds especially the compound T1 where it forms hydrogen and hydrophobic interactions with the main binding site residues. The stability of the complexes was confirmed by the MD study and the calculation of the free binding energy. The T1 synthesis reaction was carried out according to the 1,3 cycloaddition reaction. The study of the local and global reactivity and the energy of activation of this reaction have shown the predicted of the regioselectivity of compound T1. Also we have described the state of transition of two isomers T1,4 and T1.5. Finally, this study would be interesting to help identify and optimize avenues for early discovery of anticancer drugs.