Nur Intan Saidaah Mohamed Yusof, Nor Atirah Awaluddin, Fazlin Mohd Fauzi
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Then, molecular docking was performed on 10 compounds representative of each cluster. Lastly, the Spearman correlation was computed between physicochemical properties and biological activity.</p><p><strong>Results: </strong>Results showed that potent CCR5 inhibitors tend to: (i) be larger in size (molecular weight of more than 500 g/mol), (ii) bind at the deep hydrophobic pocket, mostly through π-π stacking and (iii) have more than 1 aromatic ring. The larger size may aid in reaching the deep hydrophobic pocket. However, these requirements may lead to the violation of more than 1 Lipinski's Rule of 5.</p><p><strong>Conclusion: </strong>Future studies should include analyses of the analogues or derivatives of the representative compounds to further expand on the findings here and establish the structure-activity relationship for CCR5 inhibition. This would aid in the development of new AD drugs since drug discovery and development of AD drugs are suffering from high attrition.</p>","PeriodicalId":9799,"journal":{"name":"Central nervous system agents in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Insight into the Structure and Physicochemical Properties of Potent Chemokine Receptor 5 Inhibitors for the Discovery of Novel Alzheimer's Disease Drugs.\",\"authors\":\"Nur Intan Saidaah Mohamed Yusof, Nor Atirah Awaluddin, Fazlin Mohd Fauzi\",\"doi\":\"10.2174/1871524923666230726102846\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>In Alzheimer's Disease (AD), chemokines recruit pro-inflammatory mediators and increase the aggregation of both Aβ (amyloid-β) plaque and neurofibrillary tangles (NFTs). 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引用次数: 0
摘要
背景:在阿尔茨海默病(AD)中,趋化因子募集促炎介质,并增加Aβ(淀粉样蛋白-β)斑块和神经原纤维缠结(NFT)的聚集。趋化因子受体5(CCR5)已被证明参与神经炎症和神经免疫学,其抑制作用可增强记忆、可塑性和学习能力。目的:在本研究中,分析了从ChEMBL数据库中获得的抑制CCR5的化合物,特别是特定的亚结构和物理化学性质是否与生物活性相关。方法:首先对1237个化合物进行聚类,根据它们的结构相似性将它们分为10个聚类。然后,对代表每个簇的10个化合物进行分子对接。最后,计算了理化性质和生物活性之间的Spearman相关性。结果:结果表明,强效CCR5抑制剂倾向于:(i)尺寸更大(分子量超过500 g/mol),(ii)主要通过π-π堆积结合在深疏水口袋,(iii)具有1个以上的芳环。较大的尺寸可能有助于到达深层疏水口袋。然而,这些要求可能会导致违反1 Lipinski’s Rule of 5。结论:未来的研究应包括对代表性化合物的类似物或衍生物的分析,以进一步扩展此处的发现,并建立CCR5抑制的构效关系。这将有助于开发新的AD药物,因为AD药物的药物发现和开发正遭受高损耗。
Insight into the Structure and Physicochemical Properties of Potent Chemokine Receptor 5 Inhibitors for the Discovery of Novel Alzheimer's Disease Drugs.
Background: In Alzheimer's Disease (AD), chemokines recruit pro-inflammatory mediators and increase the aggregation of both Aβ (amyloid-β) plaque and neurofibrillary tangles (NFTs). Chemokine receptor 5 (CCR5) has been demonstrated to be involved in neuroinflammation and neuroimmunology, where its inhibition was shown to enhance memory, plasticity and learning.
Objective: In this study, compounds that inhibit CCR5 obtained from the ChEMBL database were analysed, specifically for whether specific substructures and physicochemical properties are correlated to biological activity.
Methods: Clustering was first performed to group 1,237 compounds into 10 clusters based on the similarities of their structure. Then, molecular docking was performed on 10 compounds representative of each cluster. Lastly, the Spearman correlation was computed between physicochemical properties and biological activity.
Results: Results showed that potent CCR5 inhibitors tend to: (i) be larger in size (molecular weight of more than 500 g/mol), (ii) bind at the deep hydrophobic pocket, mostly through π-π stacking and (iii) have more than 1 aromatic ring. The larger size may aid in reaching the deep hydrophobic pocket. However, these requirements may lead to the violation of more than 1 Lipinski's Rule of 5.
Conclusion: Future studies should include analyses of the analogues or derivatives of the representative compounds to further expand on the findings here and establish the structure-activity relationship for CCR5 inhibition. This would aid in the development of new AD drugs since drug discovery and development of AD drugs are suffering from high attrition.
期刊介绍:
Central Nervous System Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new central nervous system agents. Containing a series of timely in-depth reviews written by leaders in the field covering a range of current topics, Central Nervous System 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 the field.