3D-QSAR assisted identification of selective CYP1B1 inhibitors: an effective bioisosteric replacement/molecular docking/electrostatic complementarity analysis

Cytochrome P450-1B1 is a majorly overexpressed drug-metabolizing enzyme in tumors and is responsible for inactivation and subsequent resistance to a variety of anti-cancer drugs, i.e., docetaxel, tamoxifen, and cisplatin. In the present study, a 3D quantitative structure-activity relationship (3D-QSAR) model has been constructed for the identification, design, and optimization of novel CYP1B1 inhibitors. The model has been built using a set of 148 selective CYP1B1 inhibitors. The developed model was evaluated based on certain statistical parameters including q² and r² which showed the acceptable predictive and descriptive capability of the generated model. The developed 3D-QSAR model assisted in understanding the key molecular fields which were firmly related to the selective CYP1B1 inhibition. A theoretic approach for the generation of new lead compounds with optimized CYP1B1 receptor affinity has been performed utilizing bioisosteric replacement analysis. These generated molecules were subjected to a developed 3D-QSAR model to predict the inhibitory activity potentials. Furthermore, these compounds were scrutinized through the activity atlas model, molecular docking, electrostatic complementarity, molecular dynamics, and waterswap analysis. The final hits might act as selective CYP1B1 inhibitors which could address the issue of resistance. This 3D-QSAR includes several chemically diverse selective CYP1B1 receptor ligands and well accounts for the individual ligand's inhibition affinities. These features of the developed 3D-QSAR model will ensure future prospective applications of the model to speed up the identification of new potent and selective CYP1B1 receptor ligands.