Virtual Screening and Biological Evaluation of T22306 as a Potent Third-generation EGFR Inhibitor for NSCLC Treatment.

IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL
Ran Wang, Wei Ruan, Dang Fan, Li Long, Han Zhang, Min Li, Shan Xu, Linxiao Wang
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引用次数: 0

Abstract

Objectives: According to the data, mutations in EGFR-related genes are the main cause of Non-Small Cell Lung Cancer (NSCLC), necessitating the development of new drug constructs for EGFR-TKIs particularly important. This study aimed to screen potential third-generation EGFR-TKIs to address the emerging drug resistance challenges in NSCLC.

Methods: In this study, virtual screening, molecular dynamics modeling, and bioactivity evaluation were carried out to find a potential EGFR inhibitor that could overcome the L858R/T790M mutation. At first, 12 potential compounds were screened step by step from about 250,000 structures by virtual screening. These 12 compounds were subjected to MTT antitumor activity evaluation and kinase inhibition assay to select compounds with strong antiproliferative effects on cancer cells. Then, the preferred compounds were subjected to time-dependent assay, scratch assay, AO staining assay, and hemolysis assay. Finally, the preferred compound was subjected to molecular docking and molecular dynamics simulation with 5HG7 protein.

Result: The IC50 of T22306 on H1975 cells was 9.17 μM. In further kinase evaluation, the kinase inhibition of EGFRL858R/T790M was 69.17%. In addition, time-dependent experiments and scratch and AO staining assays confirmed the potential of T22306 as an EGFR-TKI inhibitor, while hemolysis assays demonstrated no significant toxicity. Finally, molecular docking revealed the formation of critical hydrogen bonds between T22306 and LEU-718. Furthermore, molecular dynamics simulations showed that the T22306-5HG7 complex has a low binding energy (-117.73 ± 18.69 kJ/mol), thus suggesting that T22306 binds tightly to the target protein 5HG7.

Conclusion: In this study, we rapidly screened potential compounds against NSCLC with the help of virtual screening technology. Further in vitro experiments demonstrated that T22306 successfully overcame the L858R/T790M mutation and could be a potential epidermal growth factor receptor inhibitor.

T22306作为有效的第三代EGFR抑制剂治疗NSCLC的虚拟筛选和生物学评价
目的:资料显示,egfr相关基因突变是导致非小细胞肺癌(NSCLC)的主要原因,因此开发针对EGFR-TKIs的新药构建体尤为重要。本研究旨在筛选潜在的第三代EGFR-TKIs,以解决NSCLC中新出现的耐药挑战。方法:本研究通过虚拟筛选、分子动力学建模和生物活性评价等方法,寻找能够克服L858R/T790M突变的潜在EGFR抑制剂。首先,通过虚拟筛选,从约25万个结构中逐步筛选出12个潜在化合物。对12种化合物进行MTT抗肿瘤活性评价和激酶抑制实验,筛选出对癌细胞具有较强抗增殖作用的化合物。然后,对优选化合物进行时间依赖性试验、划痕试验、AO染色试验和溶血试验。最后,优选化合物与5HG7蛋白进行分子对接和分子动力学模拟。结果:T22306对H1975细胞的IC50为9.17 μM。在进一步的激酶评估中,EGFRL858R/T790M的激酶抑制率为69.17%。此外,时间依赖性实验、划痕和AO染色实验证实了T22306作为EGFR-TKI抑制剂的潜力,而溶血实验显示没有明显的毒性。最后,分子对接发现T22306与LEU-718之间形成了临界氢键。此外,分子动力学模拟表明,T22306-5HG7复合物具有较低的结合能(-117.73±18.69 kJ/mol),表明T22306与靶蛋白5HG7结合紧密。结论:在本研究中,我们借助虚拟筛选技术快速筛选了潜在的抗NSCLC化合物。进一步的体外实验表明,T22306成功克服了L858R/T790M突变,可能是一种潜在的表皮生长因子受体抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Anti-cancer agents in medicinal chemistry
Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL
CiteScore
5.10
自引率
3.60%
发文量
323
审稿时长
4-8 weeks
期刊介绍: Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.
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