• CCR5;
  • Piperidinecarboxamides;
  • QSAR;
  • TSAR


Chemokines receptors have emerged as important drug targets for the development of agents against the Human Immunodeficiency Virus (HIV)/AIDS pandemic. With the purpose of designing new chemical entities with enhanced antiretroviral potencies, the Quantitative Structure–Activity Relationships (QSAR) study carried out on 122 novel piperidin-4-carboxamide derivatives as antagonists of HIV Chemokine Receptor 5 (CCR5) coreceptor binding is presented. The developed model was validated by standard QSAR parameters and through a detailed structural investigation on how it explains and reproduces the quantitative differences observed in the experimentally known activity data. The model showed a good correlative and predictive ability having a cross-validated correlation coefficient (r2cv) of 0.794 and the conventional correlation coefficient (r2) was found to be 0.830. The study revealed that the CCR5 antagonistic activity exhibited by the series is largely explained by lipophilicity and steric bulkiness of substituents and that substituents with higher lipophilicity and steric superiority are required to make favorable antagonist–CCR5 interaction 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.