Ahmad Shahnawaz, Hassan Md Imtaiyaz, Gupta Dinesh, Dwivedi Neeraj, Islam Asimul
School of Biotechnology, College of Engineering and Technology, IFTM University, Lodhipur-Rajput, Delhi Road (NH-24), Moradabad, Uttar Pradesh 244102 India.
Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025 India.
3 Biotech. 2022 Sep;12(9):182. doi: 10.1007/s13205-022-03231-1. Epub 2022 Jul 19.
The protein ATP-binding cassette subfamily G member 2 (ABCG2) is one of the major factors behind multidrug resistance (MDR) in breast cancer. We performed three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, docking, and molecular dynamics (MD) simulation to design pyrimidine-based ABCG2 antagonists. The developed QSAR model ( = 0.92, = 0.82, and good cross-validated = 0.73) dictate requirement of electrostatic, and hydrophobic fields for modulating bioactivity. Based on this rationale, we designed and screened 1010 new compounds, among them 2 (ND-510 and ND-500) exhibit excellent drug-like features. Comparative molecular docking, MM/GBSA and ADMET profiles were determined to understand the interactive poses, affinity, and drug-likeness of the designed compounds. Furthermore, MD simulations were performed with the ABCG2 receptor, and the results were compared with the two earlier synthesized active compounds. The outcomes of the study will help researchers to develop new antagonists for treatment of MDR breast cancer.
The online version contains supplementary material available at 10.1007/s13205-022-03231-1.
蛋白质ATP结合盒亚家族G成员2（ABCG2）是乳腺癌多药耐药（MDR）的主要因素之一。我们进行了三维定量构效关系（3D-QSAR）建模、对接和分子动力学（MD）模拟，以设计基于嘧啶的ABCG2拮抗剂。所开发的QSAR模型（R² = 0.92，Q² = 0.82，交叉验证良好，Q² = 0.73）表明调节生物活性需要静电场和疏水场。基于这一原理，我们设计并筛选了1010种新化合物，其中2种（ND-510和ND-500）具有优异的类药物特性。通过比较分子对接、MM/GBSA和ADMET图谱来了解所设计化合物的相互作用姿态、亲和力和类药物性质。此外，对ABCG2受体进行了MD模拟，并将结果与两种早期合成的活性化合物进行了比较。该研究结果将有助于研究人员开发用于治疗MDR乳腺癌的新拮抗剂。
在线版本包含可在10.1007/s13205-022-03231-1获取的补充材料。
