ORG-317 Repurposing as a Potential Agonist Targeting TMEM236 in Colorectal Cancer Treatment: Insights from Molecular Dynamics Simulation, Principal Component Analysis, and Free Energy Landscape Study.

IF 3.5 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Neha Shree Maurya, Shikha Kushwah, Amit Chaudhary, Kavita Patel, Shruti Shukla, Ashutosh Mani
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引用次数: 0

Abstract

Background and objective: Colorectal Cancer (CRC) affects the colon and rectum part of the digestive system and is a significant global health concern, with approximately 1.1 million new cases annually. It ranks second in cancer-related deaths. Studies have shown future projections of CRC cases to enhance at a worrisome rate, estimating 3.2 million new cases and 1.6 million deaths worldwide by 2040. Studies have shown the downregulation of TMEM236 in CRC, and this study aimed to find the agonist to restore the function of TMEM236 via the drug repurposing method.

Methods: The different molecular and structural level analyses were performed to understand how the TMEM236 expression can be restored. To obtain the molecular level data, the following analyses were employed to understand the binding affinity and agonistic behaviour of the screened drugs: molecular docking, oral toxicity prediction, Molecular Dynamics (MD) simulation, Free Energy Landscape (FEL) analysis, and g_mmpbsa.

Results: The molecular docking, oral toxicity, and molecular interaction analyses have identified db06435, db05423, and db15197 drugs from the DrugBank database to either belong to an approved or investigational class of drugs as a potential agonist for TMEM236. The MD simulation and PCA analysis had shown db05423 (ORG-317) to exhibit stable interaction with TMEM236 protein. Similar results were obtained through FEL analysis.

Conclusion: The downregulation of TMEM236 expression and its constant binding affinity with db05423 during MD simulation suggest that this drug may restore the diminished function and expression of TMEM236. Additionally, it could function as an agonist and can be used for CRC treatment.

.

作为潜在的激动剂靶向TMEM236治疗结直肠癌:来自分子动力学模拟、主成分分析和自由能景观研究的见解
背景与目的:结直肠癌(CRC)影响消化系统的结肠和直肠部分,是一个重要的全球健康问题,每年约有110万新病例。它在癌症相关死亡中排名第二。研究表明,未来对结直肠癌病例的预测将以令人担忧的速度增加,估计到2040年全球将有320万新病例和160万死亡。已有研究表明TMEM236在结直肠癌中下调,本研究旨在通过药物再利用的方法寻找恢复TMEM236功能的激动剂。方法:通过不同分子和结构水平的分析,了解如何恢复TMEM236的表达。为了获得分子水平的数据,我们通过以下分析来了解筛选药物的结合亲和力和拮抗行为:分子对接、口服毒性预测、分子动力学(MD)模拟、自由能景观(FEL)分析和g_mmpbsa。结果:分子对接,口服毒性和分子相互作用分析已经从DrugBank数据库中确定db06435, db05423和db15197药物属于已批准或正在研究的药物类别,可作为TMEM236的潜在激动剂。MD模拟和PCA分析表明,db05423 (ORG-317)与TMEM236蛋白具有稳定的相互作用。FEL分析也得到了类似的结果。结论:在MD模拟过程中,TMEM236表达下调,并与db05423持续结合,提示该药物可恢复TMEM236功能和表达的下降。此外,它可以作为一种激动剂,可用于结直肠癌的治疗。
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来源期刊
Current medicinal chemistry
Current medicinal chemistry 医学-生化与分子生物学
CiteScore
8.60
自引率
2.40%
发文量
468
审稿时长
3 months
期刊介绍: Aims & Scope Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current 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.
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