Patra Jeevan, Keshari Amit K, Bhandare Richie R, Shaik Afzal B, Parrot Madison, Lin Shiru
Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow 226028, Uttar Pradesh, India.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P O Box 346, Ajman 346, United Arab Emirates.
ACS Omega. 2025 Apr 1;10(14):13880-13897. doi: 10.1021/acsomega.4c08366. eCollection 2025 Apr 15.
The angiogenesis phenomenon is crucial for the formation of new blood vessels in cancer cells. The cancerous cells' progress hampers other healthy cells. The main objective of this study is to explore and decipher multimodal natural compounds against VEGFR2, EphB4, FGFR-1, and TIE-2 drug targets to arrest angiogenesis and progression. The receptor-based pharmacophore modeling of VEGFR2, EphB4, FGFR-1, and TIE-2 was developed and validated through enrichment parameters. Further, the validated hypothesis allowed for screening druglike natural product databases such as SuperNatural 3.0, COCONUT, and LOTUS. The common pharmacophoric featured natural compounds were assessed for binding affinities using absolute end-point methods. Finally, density functional theory has been studied to understand the chemical reactivity and stability of the protein complexes. Among all of the screened natural compounds, 17 natural compounds were found to align accurately against validated pharmacophore models having higher fitness scores and align scores. Taking reference drugs sorafenib (VEGFR2), NVP-BHG712 (EphB4), pemiganitib (FGFR-1), and DP1919 (TIE-2), three promising natural compounds CNP0003920, CNP0243075, and CNP0211397 were concluded based on their end-point binding energies, binding interactions, molecular dynamics, and optimal pharmacokinetic and toxicity profiles. The density functional theory (DFT) results suggested that the identified compounds bound with protein complexes are stable. Our findings can represent a promising starting point for developing multimodal analogues VEGFR2, EphB4, FGFR-1, and TIE-2 proteins.
血管生成现象对于癌细胞中新血管的形成至关重要。癌细胞的进展会阻碍其他健康细胞。本研究的主要目的是探索和解读针对血管内皮生长因子受体2（VEGFR2）、EphB4、成纤维细胞生长因子受体1（FGFR-1）和酪氨酸激酶受体2（TIE-2）药物靶点的多模态天然化合物，以阻止血管生成和进展。通过富集参数开发并验证了基于受体的VEGFR2、EphB4、FGFR-1和TIE-2药效团模型。此外，经过验证的假设允许筛选类似药物的天然产物数据库，如SuperNatural 3.0、COCONUT和LOTUS。使用绝对终点法评估具有共同药效团特征的天然化合物的结合亲和力。最后，研究了密度泛函理论以了解蛋白质复合物的化学反应性和稳定性。在所有筛选出的天然化合物中，发现有17种天然化合物能够准确地与经过验证的药效团模型对齐，具有更高的适应度分数和对齐分数。以索拉非尼（VEGFR2）、NVP-BHG712（EphB4）、培米加替尼（FGFR-1）和DP1919（TIE-2）作为参考药物，根据其终点结合能、结合相互作用、分子动力学以及最佳药代动力学和毒性特征，得出了三种有前景的天然化合物CNP0003920、CNP0243075和CNP0211397。密度泛函理论（DFT）结果表明，所鉴定的化合物与蛋白质复合物的结合是稳定的。我们的研究结果可为开发多模态VEGFR2、EphB4、FGFR-1和TIE-2蛋白类似物提供一个有前景的起点。
