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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.


(a) Common pharmacophore for active ligands [one hydrogen bond acceptor (A) in pink color, one positive center (P) in sky blue color, and three aromatic rings (R) in yellow color]. (b) 2D representation of pharmacophore
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Figure 2: (a) Common pharmacophore for active ligands [one hydrogen bond acceptor (A) in pink color, one positive center (P) in sky blue color, and three aromatic rings (R) in yellow color]. (b) 2D representation of pharmacophore

Mentions: The best pharmacophore hypothesis APRRR-105 [Figure 2] was selected for further QSAR study. The above-mentioned 3D pharmacophore hypothesis [Figure 2a] encompasses the following features: One hydrogen bond acceptor (A) in pink color, one positive center (P) in sky blue color, and three aromatic rings (R) in yellow color. The 2D representation of the APRRR-105 hypothesis is given in Figure 2b. The 2D representation shows that the three aromatic rings (A, B, and C of benzotriazole and the distal phenyl ring), one positive center (piperazine), one hydrogen bond acceptor and the carbonyl functional group attached to the benzotriazole ring are the pharmacophoric elements of APRRR-105 hypothesis.


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)

(a) Common pharmacophore for active ligands [one hydrogen bond acceptor (A) in pink color, one positive center (P) in sky blue color, and three aromatic rings (R) in yellow color]. (b) 2D representation of pharmacophore
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: (a) Common pharmacophore for active ligands [one hydrogen bond acceptor (A) in pink color, one positive center (P) in sky blue color, and three aromatic rings (R) in yellow color]. (b) 2D representation of pharmacophore
Mentions: The best pharmacophore hypothesis APRRR-105 [Figure 2] was selected for further QSAR study. The above-mentioned 3D pharmacophore hypothesis [Figure 2a] encompasses the following features: One hydrogen bond acceptor (A) in pink color, one positive center (P) in sky blue color, and three aromatic rings (R) in yellow color. The 2D representation of the APRRR-105 hypothesis is given in Figure 2b. The 2D representation shows that the three aromatic rings (A, B, and C of benzotriazole and the distal phenyl ring), one positive center (piperazine), one hydrogen bond acceptor and the carbonyl functional group attached to the benzotriazole ring are the pharmacophoric elements of APRRR-105 hypothesis.

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.