Docking, molecular dynamics simulation studies, and structure-based QSAR model on cytochrome P450 2A6 inhibitors

In this study, we used molecular docking and molecular dynamics (MD) simulation studies to analyze the interactions of a series of naphthalene and non-naphthalene derivatives ( n = 38) as potent inhibitors of cytochrome P450 2A6 (CYP2A6) and to construct a structure-based quantitative structure activity relationship (QSAR) model. A 6000 ps MD simulation in a cubic water box were employed to build 3D structure of the CYP2A6 in a water environment. After reaching the equilibrium, the most potent inhibitor (2-bromonaphthalene) was docked into the CYP2A6 to realize the binding site of the enzyme. The docking analysis showed that π – π interaction of the inhibitors with four phenylalanine residues at positions of 107, 111, 118, and 480 plays an important role in the activities of the inhibitors. Then, an additional 6000 ps MD simulation was performed on the complex of the CYP2A6–2-bromonaphthalene to explore the effect of the inhibitor on the stability of the protein–inhibitor complex. Radius of gyration values for CYP2A6 and CYP2A6–2-bromonaphthalene complex were 2.23 ± 0.01 and 2.21 ± 0.01 nm, respectively, which revealed that the structure of the CYP2A6 in the presence of 2-bromonaphthalene has not changed. Finally, all the inhibitors docked into the enzyme and the docked configuration of the inhibitors with the lowest free energy was used to calculate the most feasible descriptors. The selected descriptors were related to the inhibitory activities using multiple linear regression (MLR) and least squares support vector regression (LS-SVR) models. The Q 2 values for MLR and LS-SVR were 0.695 and 0.728, respectively.