Phosphorus-substituted Quinoline Derivatives as Topoisomerase I Inhibitors: QSAR Modeling, Molecular Docking, and Molecular Dynamic Simulation

Topoisomerase plays essential roles in cellular reproduction and DNA organization by facilitating the cleavage of single and double stranded DNA to relax supercoils, unwind catenanes, and condense chromosomes in eukaryotic cells. These complexes are cytotoxic agents because the unrepaired single and double stranded DNA breaks they produce may cause apoptosis and cell death.

This work employs multiple linear regression, principal component regression, and partial least squares to investigate the quantitative structure-activity relationship (QSAR) of 28 compounds derived from phosphorus-substituted quinoline. Evidence for the modeling was found in the correlation between the anti-proliferative activity and several electronic and structural properties of the molecules, including EHOMO (energy of the highest occupied molecular orbital) and ELUMO (energy of the lowest unoccupied molecular orbital).

These electronic properties were calculated using the Density Functional Theory (DFT) approach at the B3LYP/6-31G (d, p) level of theory. Principal Component Analysis (PCA) was utilized to test for collinearity between the descriptors. Actually, using different counts of 2D and 3D descriptors, three alternative prediction models were constructed, and each one was evaluated using the statistical metrics of root mean square error (RMSE) and coefficient of determination (R2). With an R2 of 0.865 and an RMSE of 0.316, respectively, an MLR model demonstrated the highest predictive performance of all the models that were built.

By using crystal structure modeling, three proteins (6G77, 2NS2, and 5K47) for lung, ovarian, and kidney cancers demonstrated strong binding affinities via hydrophobic interactions and H-bonds with the relevant chemicals. The compounds with the highest binding energies for lung, kidney, and ovarian cancer were C11, C19, and C26, in that order. The molecular docking results from previous studies, which showed that inhibitors were stable in the active sites of the chosen proteins for 10 ns, were supported by the results of the molecular dynamic MD simulation diagram. This suggests that these compounds might be a useful model for creating and synthesizing novel, potent anticancer compounds.