细胞色素P450-1B1是肿瘤中主要过度表达的药物代谢酶,负责失活和随后对多种抗癌药物的耐药性,即,多西他赛,他莫昔芬,和顺铂.在本研究中,建立了三维定量结构-活性关系(3D-QSAR)模型,设计,并优化了新型CYP1B1抑制剂。该模型是使用一组148种选择性CYP1B1抑制剂建立的。基于包括q2和r2的某些统计参数来评价所开发的模型,其显示所生成的模型的可接受的预测和描述能力。开发的3D-QSAR模型有助于理解与选择性CYP1B1抑制密切相关的关键分子领域。已利用生物等排替代分析进行了具有优化的CYP1B1受体亲和力的新先导化合物的产生理论方法。对这些产生的分子进行开发的3D-QSAR模型以预测抑制活性潜力。此外,这些化合物通过活性图谱模型进行了仔细检查,分子对接,静电互补,分子动力学,和换水分析。最终命中可能充当选择性CYP1B1抑制剂,其可以解决抗性问题。这种3D-QSAR包括几种化学上不同的选择性CYP1B1受体配体,并很好地解释了单个配体的抑制作用。开发的3D-QSAR模型的这些特征将确保该模型的未来应用,以加快新的有效和选择性CYP1B1受体配体的鉴定。
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.