Publication

Abstract : The CCR5 chemokine receptor has recently been found to play a crucial role in the viral entry stage of HIV infection and has therefore become an attractive potential target for anti-HIV therapeutics. On the other hand, the lack of CCR5 crystal structure data has impeded the development of structure-based CCR5 antagonist design. In this paper, we compare two three-dimensional Quantitative Structure–Activity Relationship (3D-QSAR) methods: Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) on a series of piperidine-based CCR5 antagonists as an alternative approach to investigate the interaction between CCR5 antagonists and their receptor. Superimposition of antagonist structures was performed using two alignment rules: atomic/centroid rms fit and rigid body field fit techniques. The 3D QSAR models were derived from a training set of 72 compounds, and were found to have predictive capability for a set of 19 holdout test compounds. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to biological activity in this series of compounds. Further analyses of these interaction-field contour maps also showed a high level of internal consistency. 3D-QSAR models have been built for a series of piperidine-based CCR5 antagonists using CoMFA and CoMSIA approaches. The derived 3D-QSAR models showed predictive capabilities and a high level of internal consistency. The resulting contour maps can be used to identify structural features relevant to binding affinity, and can aid in the future development of potential anti-HIV agents.