Insight into the Structure and Physicochemical Properties of Potent Chemokine Receptor 5 Inhibitors for the Discovery of Novel Alzheimer’s Disease Drugs

• Published in: Central Nervous System Agents in Medicinal Chemistry
• Main Author: Yusof N.I.S.M.; Awaluddin N.A.; Fauzi F.M.
• Format: Article
• Language: English
• Published: Bentham Science Publishers 2023
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85172425864&doi=10.2174%2f1871524923666230726102846&partnerID=40&md5=b745acb10d4f6855f36774a6a420297f

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.