Investigation of the Structural Requirement for Blocking the Human CCR5 Chemokine Receptor. An Insight from Quantitative Structure Activity Relationships Study

摘要

Chemokines receptors have emerged as promising targets for discovery of agents against the HIV/AIDS pandemic. With the purpose of designing new chemical entities with enhanced potencies against the CCR5 chemokine receptor, the QSAR study carried out on 42 novel piperazine derivatives as antagonists of CCR5 HIV co receptor is presented. The developed model was validated by standard QSAR parameters and through a detailed structural investigation on how it reproduces and explains the quantitative differences seen in experimentally known pharmacological data. The model showed a good correlative and predictive ability having a cross validated correlation co-efficient (r2 cv) of 0.768 and a conventional correlation co-efficient (r2) of 0.914. The predictive correlation coefficient (r2 pred) was found to be 0.654. The study revealed that the CCR5 antagonistic activity exhibited by the series is largely explained by steric factors and lipophilicities of substituents and emphasized the role of substituent size and shape in forming effective antagonist-CCR5 binding chemistry. A detailed investigation was made on the structural basis for the antiretroviral activity and the insights gleaned from the study could be usefully employed to design antagonists with a much more enhanced potency and selectivity.