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3D-QSAR study of benzotriazol-1-yl carboxamide scaffold as monoacylglycerol lipase inhibitors.

Afzal O, Kumar S, Kumar R, Jaggi M, Bawa S - J Pharm Bioallied Sci (2014)

Bottom Line: A 3D-QSAR study on benztriazol-1-yl carboxamide derivatives as monoacylglycerol lipase (MAGL) inhibitors was successfully performed by means of pharmacophore mapping using PHASE 3.5 module of Schrφdinger-9.4.The 3D-QSAR obtained from APRRR-105 hypothesis was found to be statistically good with r(2) = 0.9228 and q(2) = 0.871, taking PLS factor 4.Thus, it can be assumed that the present QSAR analysis is enough to demonstrate MAGL inhibition with the help of APRRR-105 hypothesis and will be helpful in designing novel and potent MAGL inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi, India.

ABSTRACT

Purpose: The purpose of this study is to build up the 3D pharmacophore of Monoacylglycerol lipase (MAGL) inhibitor and to provide the basis to design the novel and potent MAGL inhibitors.

Material and method: A 3D-QSAR study on benztriazol-1-yl carboxamide derivatives as monoacylglycerol lipase (MAGL) inhibitors was successfully performed by means of pharmacophore mapping using PHASE 3.5 module of Schrφdinger-9.4.

Result: The 3D-QSAR obtained from APRRR-105 hypothesis was found to be statistically good with r(2) = 0.9228 and q(2) = 0.871, taking PLS factor 4. The statistical significance of the model was also confirmed by a high value of Fisher's ratio of 82.8 and a very low value of root-mean-square error (RMSE) 0.2564. Another parameter which signifies the model predictivity is Pearson R. Its value of 0.9512 showed that the correlation between predicted and observed activities for the test set compounds is excellent.

Conclusion: The study suggested that one H-bond acceptor, one positive center, and proper positioning of hydrophobic groups near the distal aromatic ring C are the crucial determinants for MAGL inhibition. Thus, it can be assumed that the present QSAR analysis is enough to demonstrate MAGL inhibition with the help of APRRR-105 hypothesis and will be helpful in designing novel and potent MAGL inhibitors.

No MeSH data available.


QSAR visualization of various substituents: (a) H-bond acceptor, (b) positive center, and (c) hydrophobic domain
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Figure 3: QSAR visualization of various substituents: (a) H-bond acceptor, (b) positive center, and (c) hydrophobic domain

Mentions: A successful 3D-QSAR study has been performed for substituted benztriazol-1-yl carboxamide derivatives to understand the effect of spatial arrangement of structural features on MAGL inhibition. Result of the 3D-QSAR is presented in Figure 3. The blue cubes in 3D plots of the 3D pharmacophore regions refer to ligand regions in which the specific feature is important for better activity, whereas the red cubes demonstrate that particular structural feature or functional group is not essential for the activity or likely to be the reason for decreased binding affinity. The statistical results of 3D-QSAR study are summarized in Table 3.


3D-QSAR study of benzotriazol-1-yl carboxamide scaffold as monoacylglycerol lipase inhibitors.

Afzal O, Kumar S, Kumar R, Jaggi M, Bawa S - J Pharm Bioallied Sci (2014)

QSAR visualization of various substituents: (a) H-bond acceptor, (b) positive center, and (c) hydrophobic domain
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4231386&req=5

Figure 3: QSAR visualization of various substituents: (a) H-bond acceptor, (b) positive center, and (c) hydrophobic domain
Mentions: A successful 3D-QSAR study has been performed for substituted benztriazol-1-yl carboxamide derivatives to understand the effect of spatial arrangement of structural features on MAGL inhibition. Result of the 3D-QSAR is presented in Figure 3. The blue cubes in 3D plots of the 3D pharmacophore regions refer to ligand regions in which the specific feature is important for better activity, whereas the red cubes demonstrate that particular structural feature or functional group is not essential for the activity or likely to be the reason for decreased binding affinity. The statistical results of 3D-QSAR study are summarized in Table 3.

Bottom Line: A 3D-QSAR study on benztriazol-1-yl carboxamide derivatives as monoacylglycerol lipase (MAGL) inhibitors was successfully performed by means of pharmacophore mapping using PHASE 3.5 module of Schrφdinger-9.4.The 3D-QSAR obtained from APRRR-105 hypothesis was found to be statistically good with r(2) = 0.9228 and q(2) = 0.871, taking PLS factor 4.Thus, it can be assumed that the present QSAR analysis is enough to demonstrate MAGL inhibition with the help of APRRR-105 hypothesis and will be helpful in designing novel and potent MAGL inhibitors.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University, New Delhi, India.

ABSTRACT

Purpose: The purpose of this study is to build up the 3D pharmacophore of Monoacylglycerol lipase (MAGL) inhibitor and to provide the basis to design the novel and potent MAGL inhibitors.

Material and method: A 3D-QSAR study on benztriazol-1-yl carboxamide derivatives as monoacylglycerol lipase (MAGL) inhibitors was successfully performed by means of pharmacophore mapping using PHASE 3.5 module of Schrφdinger-9.4.

Result: The 3D-QSAR obtained from APRRR-105 hypothesis was found to be statistically good with r(2) = 0.9228 and q(2) = 0.871, taking PLS factor 4. The statistical significance of the model was also confirmed by a high value of Fisher's ratio of 82.8 and a very low value of root-mean-square error (RMSE) 0.2564. Another parameter which signifies the model predictivity is Pearson R. Its value of 0.9512 showed that the correlation between predicted and observed activities for the test set compounds is excellent.

Conclusion: The study suggested that one H-bond acceptor, one positive center, and proper positioning of hydrophobic groups near the distal aromatic ring C are the crucial determinants for MAGL inhibition. Thus, it can be assumed that the present QSAR analysis is enough to demonstrate MAGL inhibition with the help of APRRR-105 hypothesis and will be helpful in designing novel and potent MAGL inhibitors.

No MeSH data available.