QSAR studies on CCR2 antagonists with chiral sensitive hologram descriptors

Chemokines are small molecular weight water-soluble proteins playing a key role in immunomodulation and host-defense mechanisms. CCR2 receptor is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. Reported, herein are the QSAR studies performed on a diverse set of enantiopure analogues reported as CCR2 antagonists by hologram analysis. The best model highlights the importance of chirality feature in comparison with the other models developed without the chirality. The validated model showed high internal and external predictive power. The robustness of the model was achieved with good statistical r2 of 0.945 and cross-validated rcv2 of 0.837. The challenging test predictivity of the model was confirmed with rpred2 of 0.807. The fragment fingerprints help in understanding essential pharmacophoric features for CCR2 antagonism and provide basis for SAR of the molecules. The 2D contribution maps with fragment information will be useful for the design of novel CCR2 antagonists having improved efficacy.

The manuscript reports holographic QSAR studies on CCR2 antagonists with the importance of chirality parameter in model building. The significance of the generated fragments with its relative contributions provides an insight to distinguish S isomer from R counterpart. The fragment information provides useful clues for the design of novel CCR2 antagonists.Figure optionsDownload as PowerPoint slide