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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.


Established MAGL inhibitors JZL184 and SAR629
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Figure 1: Established MAGL inhibitors JZL184 and SAR629

Mentions: Monoacylglycerol lipase (MAGL) is a serine hydrolase 33 kDa enzyme consisting of 303 amino acids. It hydrolyzes monoacylglycerols to glycerol and fatty acid through a catalytic triad mechanism consisting of the amino acids, Ser122, Asp239, and His269. It is a cytosolic enzyme that is also associated with membranes, with the highest expression in brain, white adipose tissue, and liver.[1234] One of these monoacylglycerols is the endocannabinoid, 2-arachidonoylglycerol (2-AG), an endogenous full agonist at CB1 and CB2 G-protein coupled receptors.[56] Pathophysiological role of MAGL has been greatly studied in current years due to the accessibility of highly potent and selective inhibitors such as JZL184 and SAR629 [Figure 1], as well as the development of MAGL-deficient (−/−) mice.[789] Pharmacological or genetic knockdown of MAGL lowers 2-AG hydrolytic activity by more than 80% in most tissues including the brain, while the remaining 20% of 2-AG hydrolytic activity in brain arises from the uncharacterized serine hydrolases α/β hydrolase domain 6, ABHD6 and ABHD12.[1011] MAGL-mediated hydrolysis of the 2-AG provides the major arachidonic acid (AA) precursor for pro-inflammatory eicosanoid synthesis in specific tissues.[1213] Studies in recent years have shown that MAGL inhibitors elicit antinociceptive, anxiolytic, and antiemetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through attractive endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration by decreasing eicosanoid production.[1415161718] In cancer, MAGL inhibitors have been shown to have anticancer properties not only through modulating the endocannabinoid–eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids like phosphatidic acid (PA), lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), and prostaglandins PGE2 and PGD2.[12] These stimulating findings suggest that pharmacological inhibition of MAGL may provide considerable therapeutic benefit.


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)

Established MAGL inhibitors JZL184 and SAR629
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Established MAGL inhibitors JZL184 and SAR629
Mentions: Monoacylglycerol lipase (MAGL) is a serine hydrolase 33 kDa enzyme consisting of 303 amino acids. It hydrolyzes monoacylglycerols to glycerol and fatty acid through a catalytic triad mechanism consisting of the amino acids, Ser122, Asp239, and His269. It is a cytosolic enzyme that is also associated with membranes, with the highest expression in brain, white adipose tissue, and liver.[1234] One of these monoacylglycerols is the endocannabinoid, 2-arachidonoylglycerol (2-AG), an endogenous full agonist at CB1 and CB2 G-protein coupled receptors.[56] Pathophysiological role of MAGL has been greatly studied in current years due to the accessibility of highly potent and selective inhibitors such as JZL184 and SAR629 [Figure 1], as well as the development of MAGL-deficient (−/−) mice.[789] Pharmacological or genetic knockdown of MAGL lowers 2-AG hydrolytic activity by more than 80% in most tissues including the brain, while the remaining 20% of 2-AG hydrolytic activity in brain arises from the uncharacterized serine hydrolases α/β hydrolase domain 6, ABHD6 and ABHD12.[1011] MAGL-mediated hydrolysis of the 2-AG provides the major arachidonic acid (AA) precursor for pro-inflammatory eicosanoid synthesis in specific tissues.[1213] Studies in recent years have shown that MAGL inhibitors elicit antinociceptive, anxiolytic, and antiemetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through attractive endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration by decreasing eicosanoid production.[1415161718] In cancer, MAGL inhibitors have been shown to have anticancer properties not only through modulating the endocannabinoid–eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids like phosphatidic acid (PA), lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), and prostaglandins PGE2 and PGD2.[12] These stimulating findings suggest that pharmacological inhibition of MAGL may provide considerable therapeutic benefit.

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.