Structural refinement and prediction of potential CCR2 antagonists through validated multi-QSAR modeling studies

Abstract

Chemokines trigger numerous inflammatory responses and modulate the immune system. The interaction between monocyte chemoattractant protein-1 and chemokine receptor 2 (CCR2) may be the cause of atherosclerosis, obesity, and insulin resistance. However, CCR2 is also implicated in other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma, and neuropathic pain. Therefore, there is a paramount importance of designing potent and selective CCR2 antagonists despite a number of drug candidates failed in clinical trials. In this article, 83 CCR2 antagonists by Jhonson and Jhonson Pharmaceuticals have been considered for robust validated multi-QSAR modeling studies to get an idea about the structural and pharmacophoric requirements for designing more potent CCR2 antagonists. All these QSAR models were validated and statistically reliable. Observations resulted from different modeling studies correlated and validated results of other ones. Finally, depending on these QSAR observations, some new molecules were proposed that may exhibit higher activity against CCR2.

Keywords:

• CCR2 antagonist
• 2D-QSAR
• Bayesian classification
• pharmacophore mapping
• CoMFA
• CoMSIA

Acknowledgments

Mr. Nilanjan Adhikari is thankful to University Grants Commission (UGC), New Delhi for providing Rajiv Gandhi National Fellowship (RGNF). Prof. Tarun Jha is thankful for the financial support from University with Potential for Excellence (UPE) Phase II Program of UGC, New Delhi to Jadavpur University, Kolkata, India. We also thank the support from Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India and Department of Pharmaceutical Sciences, Dr. Harisingh Gour University, Sagar, India for providing research facilities.