Sharma Neha, Mazumder Rupa, Rai Pallavi, Debnath Abhijit
Noida Institute of Engineering and Technology (Pharmacy Institute), 19 Knowledge Park-II, Institutional Area, Greater Noida, 201306, Uttar Pradesh, India.
Department of Pharmacy, Ram-Eesh Institute of Vocational and Technica Education, Plot No. 3, Knowledge Park - I, Kasna Road, Greater Noida, Gautam Budh Nagar, 201310, Uttar Pradesh, India.
Curr Comput Aided Drug Des. 2025 Jan 6. doi: 10.2174/0115734099312638240830060525.
Squamous cell carcinoma is a major public health concern, with traditional treatments such as surgery, chemotherapy, and radiation therapy frequently resulting in significant side effects. Immunotherapy targeting checkpoints such as PD-1, CTLA-4, and B7- H3 provides a more specific approach but incurs high costs due to monoclonal antibodies.
This study aims to investigate the potential of natural flavonoids as lowtoxicity, small molecule-based alternatives targeting the PD-1 immunological checkpoint for SCC treatment. It aims to identify and evaluate flavonoid compounds from the NPACT database for their efficacy through in silico and in vitro screenings.
Employing a comprehensive in silico approach, including SBVS, Drug Likeness, Toxicity Prediction, Consensus Molecular Docking, DFT, and 300 ns MD simulations, this study screened for flavonoids with high affinity to PD-1. Identified lead molecules were further validated through in-vitro assays, such as NRU, to assess their anticancer activities.
The flavonoid NPACT01407 showed high affinity for PD-1, favorable drug-like properties, low toxicity, and effective stability at the active site, along with an optimal IC50 value, highlighting its potential as an effective immunotherapeutic agent for SCC.
The study highlights the potential of the flavonoid molecule NPACT01407 as a promising candidate for the immunotherapeutic treatment of Squamous cell carcinoma. These findings provide a solid basis for further experimental validation and drug development efforts, suggesting a novel, less toxic, and cost-effective approach to cancer treatment.
鳞状细胞癌是一个重大的公共卫生问题，手术、化疗和放疗等传统治疗方法常常会导致严重的副作用。针对程序性死亡受体 1（PD-1）、细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）和 B7-H3 等免疫检查点的免疫疗法提供了一种更具特异性的方法，但由于单克隆抗体，成本很高。
本研究旨在探讨天然黄酮类化合物作为低毒性、基于小分子的替代物靶向 PD-1 免疫检查点用于鳞状细胞癌治疗的潜力。其目的是通过计算机模拟和体外筛选，从 NPACT 数据库中鉴定和评估黄酮类化合物的疗效。
本研究采用全面的计算机模拟方法，包括虚拟筛选（SBVS）、类药性、毒性预测、一致性分子对接、密度泛函理论（DFT）和 300 纳秒分子动力学（MD）模拟，筛选对 PD-1 具有高亲和力的黄酮类化合物。通过体外试验，如中性红摄取试验（NRU），对鉴定出的先导分子进行进一步验证，以评估其抗癌活性。
黄酮类化合物 NPACT01407 对 PD-1 表现出高亲和力、良好的类药性质、低毒性以及在活性位点的有效稳定性，同时具有最佳的半数抑制浓度（IC50）值，突出了其作为鳞状细胞癌有效免疫治疗剂的潜力。
该研究突出了黄酮类分子 NPACT01407 作为鳞状细胞癌免疫治疗有前景候选物的潜力。这些发现为进一步的实验验证和药物开发工作提供了坚实基础，表明了一种新型、低毒且具有成本效益的癌症治疗方法。
