PMID- 22557923
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121002
LR  - 20211021
IS  - 0975-7406 (Electronic)
IS  - 0976-4879 (Print)
IS  - 0975-7406 (Linking)
VI  - 4
IP  - 2
DP  - 2012 Apr
TI  - 3D-QSAR studies on CCR2B receptor antagonists: Insight into the structural 
      requirements of (R)-3-aminopyrrolidine series of molecules based on CoMFA/CoMSIA 
      models.
PG  - 123-33
LID - 10.4103/0975-7406.94813 [doi]
AB  - OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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 the standard error of 
      prediction value of 0.367, standard error of estimate 0.141, and a reliable 
      external predictivity, with a predictive r(2) (r(2) (pred)) of 0.673. While the 
      CoMSIA model yielded an r(2) (loo) of 0.719, r(2) (ncv) of 0.964,F value of 
      135.666, r(2) (bs) of 0.975, standard error of prediction of 0.512, standard 
      error of estimate of 0.180, and an external predictivity with an r(2) (pred) of 
      0.611. These validation tests not only revealed the robustness of the models but 
      also demonstrated that for our models r(2) (pred), based on the mean activity of 
      test set compounds can accurately estimate external predictivity. CONCLUSION: The 
      QSAR model gave satisfactory statistical results in terms of q(2) and r(2) 
      values. We analyzed the contour maps obtained, to study the activity trends of 
      the molecules. We have tried to demonstrate structural features of compounds to 
      account for the activity in terms of positively contributing physicochemical 
      properties such as steric, electrostatic, hydrophobic, hydrogen bond donor, and 
      acceptor fields. These contour plots identified several key features, which 
      explain the wide range of activities. The results obtained from models offer 
      important structural insight into designing novel CCR2B antagonists before their 
      synthesis.
FAU - Gade, Swetha
AU  - Gade S
AD  - Department of Botany, Bioinformatics Division, Osmania University, Hyderabad, 
      Andhra Pradesh, India.
FAU - Mahmood, Shaik
AU  - Mahmood S
LA  - eng
PT  - Journal Article
PL  - India
TA  - J Pharm Bioallied Sci
JT  - Journal of pharmacy & bioallied sciences
JID - 101537209
PMC - PMC3341716
OTO - NOTNLM
OT  - (R)-3-aminopyrrolidine series
OT  - 3D-QSAR
OT  - CCR2B
OT  - CoMFA
OT  - CoMSIA
COIS- Conflict of Interest: None declared.
EDAT- 2012/05/05 06:00
MHDA- 2012/05/05 06:01
PMCR- 2012/04/01
CRDT- 2012/05/05 06:00
PHST- 2011/01/19 00:00 [received]
PHST- 2011/05/14 00:00 [revised]
PHST- 2011/07/17 00:00 [accepted]
PHST- 2012/05/05 06:00 [entrez]
PHST- 2012/05/05 06:00 [pubmed]
PHST- 2012/05/05 06:01 [medline]
PHST- 2012/04/01 00:00 [pmc-release]
AID - JPBS-4-123 [pii]
AID - 10.4103/0975-7406.94813 [doi]
PST - ppublish
SO  - J Pharm Bioallied Sci. 2012 Apr;4(2):123-33. doi: 10.4103/0975-7406.94813.