3D-QSAR studies on CCR2B receptor antagonists: Insight into the structural requirements of (R)-3-aminopyrrolidine series of molecules based on CoMFA/CoMSIA models.

Journal of Pharmacy & Bioallied Sciences
Swetha Gade, Shaik Mahmood

Abstract

Monocyte chemo attractant protein-1 (MCP-1) is a member of the CC-chemokine family and it selectively recruits leukocytes from the circulation to the site of inflammation through binding with the chemotactic cytokine receptor 2B (CCR2B). The recruitment and activation of selected populations of leukocytes is a key feature in a variety of inflammatory conditions. Thus MCP-1 receptor antagonist represents an attractive target for drug discovery. To understand the structural requirements that will lead to enhanced inhibitory potencies, we have carried out 3D-QSAR (quantitative structure-activity relationship) studies on (R)-3-aminopyrrolidine series of molecules as CCR2B receptor antagonists. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of (R)-3-aminopyrrolidine derivatives as antagonists of CCR2B receptor with Sybyl 6.7v. We have derived statistically significant model from 37 molecules and validated it against an external test set of 13 compounds. The CoMFA model yielded a leave one out r(2) (r(2) (loo)) of 0.847, non-cross-validated r(2) (r(2) (ncv)) of 0.977, F value of 267.930, and bootstrapped r(2) (r(2) (bs)) of 0.988. We have derived ...Continue Reading

Methods Mentioned

BETA
X-ray
NMR

Software Mentioned

CoMSIA
MOPAC
Sybyl
CoMFA
Tripos

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