Shah Altaf Ahmad, Ahmad Shaban, Yadav Manoj Kumar, Raza Khalid, Kamal Mohammad Amjad, Akhtar Salman
Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, 226026, India.
Department of Computer Science, Jamia Millia Islamia, New Delhi, 110025, India.
Curr Med Chem. 2024;31(5):595-619. doi: 10.2174/0929867330666230309143711.
Epidermal growth factor receptor (EGFR/HER-1) and its role in tumor development and progression through the mechanism of tumor angiogenesis is prevalent in non-small lung cancer, head and neck cancer, cholangiocarcinoma & glioblastoma. Previous treatments targeting the oncogenic activity of EGFR's kinase domain have been hindered by acquired mutational resistance and side effects from existing drugs like erlotinib, highlighting the need for new EGFR inhibitors through structure- based drug designing.
The research aims to develop novel quinazoline derivatives through structure-based virtual screening, molecular docking, and molecular dynamics simulation to potentially interact with EGFR's kinase domain and impede tumor angiogenic phenomenon.
Quinazoline derivatives were retrieved and filtered from the PubChem database using structure- based virtual screening and the Lipinski rule of five drug-likeness studies. Molecular docking-based virtual screening methods and molecular dynamics simulation were then carried out to identify top leads.
A total of 1000 quinazoline derivatives were retrieved, with 671 compounds possessing druglike properties after applying Lipinski filters. Further filtration using ADME and toxicity filters yielded 28 compounds with good pharmacokinetic profiles. Docking-based virtual screening identified seven compounds with better binding scores than the control drug, dacomitinib. After cross-checking binding scores, three top compounds QU524, QU571, and QU297 were selected for molecular dynamics simulation study of 100 ns interval using Desmond module of Schrodinger maestro to understand their conformational stability.
The research results showed that the selected quinazoline leads exhibited better binding affinity and conformational stability than the control drug, erlotinib. These compounds also had good pharmacokinetic and pharmacodynamic profiles and did not violate Lipinski's rule of five limits. The findings suggest that these leads have the potential to target EGFR's kinase domain and inhibit the EGFR-associated phenomenon of tumor angiogenesis.
表皮生长因子受体（EGFR/HER-1）及其通过肿瘤血管生成机制在肿瘤发展和进展中的作用在非小细胞肺癌、头颈癌、胆管癌和胶质母细胞瘤中普遍存在。先前针对EGFR激酶结构域致癌活性的治疗受到获得性突变耐药性以及现有药物（如厄洛替尼）副作用的阻碍，这凸显了通过基于结构的药物设计开发新型EGFR抑制剂的必要性。
本研究旨在通过基于结构的虚拟筛选、分子对接和分子动力学模拟来开发新型喹唑啉衍生物，以使其可能与EGFR的激酶结构域相互作用并阻碍肿瘤血管生成现象。
使用基于结构的虚拟筛选和五规则类药性质研究从PubChem数据库中检索并筛选喹唑啉衍生物。然后进行基于分子对接的虚拟筛选方法和分子动力学模拟以确定最佳先导化合物。
共检索到1000种喹唑啉衍生物，应用Lipinski筛选后有671种化合物具有类药性质。使用ADME和毒性筛选进一步过滤后得到28种具有良好药代动力学特征的化合物。基于对接的虚拟筛选鉴定出7种化合物，其结合分数优于对照药物达可替尼。在交叉检查结合分数后，选择了三种最佳化合物QU524、QU571和QU297，使用Schrodinger maestro的Desmond模块进行100 ns间隔的分子动力学模拟研究，以了解它们的构象稳定性。
研究结果表明，所选的喹唑啉先导化合物比对照药物厄洛替尼表现出更好的结合亲和力和构象稳定性。这些化合物还具有良好的药代动力学和药效学特征，并且未违反Lipinski五规则限制。研究结果表明，这些先导化合物有可能靶向EGFR的激酶结构域并抑制与EGFR相关的肿瘤血管生成现象。
