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.