In-silico design novel phenylsulfonyl furoxan and phenstatin derivatives as multi-target anti-cancer inhibitors based on 2D-QSAR, molecular docking, dynamics and ADMET approaches

A series of 31 hybrid of phenylsulfonyl furoxan and phenstatin (1a-j, 2a-j, 3a-j, 4 and 5) derivatives, were computationally studied as potential anti-cancer inhibitors against four cell lines, i.e. A2780, MDA-MB-231, HCT-116 and A549. In this work, the 2D-QSAR approach combining the multiple linear regression (MLR) model, and internal and external cross-validation, showed a satisfactory quality factor: R2 = 0.85, 0.74, 0.82 and 0.75 for the four cell lines, respectively. The binding affinity of the hybrid agents towards the four 4GL7, 6GUE, 1M17 and 4XL7 anti-tumoral targets was further evaluated using molecular docking and dynamics simulations (0–200 ns). The dynamics assessment parameters indicated the formation of satisfactorily stable complexes. In addition, all considered data sets show that the best binding affinity, including the highest docking score, hydrogen bond energy and amino acid steric interactions are well predicted for the best-selected complexes. The developed 2D-QSAR model was leveraged to design and predict the biological activity of 12 new hybrid compounds (N1–N12) based on the best in-vivo inhibitor, namely, the 3 h ligand of the formula: (4-((1-(2-((4-((3crylamidophenyl)amino)quinazolin-2-yl)thio)acetyl)piperidin-4-yl)oxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide). Multitargeting docking scores and dynamics simulations show that they exhibit satisfactorily potent anti-tumoral inhibition abilities towards the four proteins. Our in-silico outcomes would be combined with in-vitro and in-vivo studies to provide a perspective on the validation of their anti-cancer activity. In particular, the ADMET predictions indicate that four new designed ligands have demonstrated a good drug-like profile and can be considered prospective candidates for future anti-cancer therapies.