| Summary: | Background: In Alzheimer’s Disease (AD), chemokines recruit pro-inflammatory me-diators 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 neuroinflamma-tion 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 repre-sentative of each cluster. Lastly, the Spearman correlation was computed between physicochemi-cal 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 hy-drophobic 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 repre-sentative 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. © 2023 Bentham Science Publishers.
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