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Bioorg Med Chem Lett. 2014 Aug 15;24(16):3986-96. doi: 10.1016/j.bmcl.2014.06.029. Epub 2014 Jun 19.

Docking based virtual screening and molecular dynamics study to identify potential monoacylglycerol lipase inhibitors.

Author information

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
2
Biomedical Informatics Center of ICMR, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
3
Dabur Research Foundation, Ghaziabad, Uttar Pradesh, India.
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi 110062, India. Electronic address: drsbawa@rediffmail.com.

Abstract

Monoacylglycerol lipase (MAGL) is one of the key enzymes of the endocannabinoid system (ECS). It hydrolyzes one of the major endocannabinoid, 2-arachidonoylglycerol (2-AG), an endogenous full agonist at G protein coupled cannabinoid receptors CB1 and CB2. Numerous studies showed that MGL inhibitors are potentially useful for the treatment of pain, inflammation, cancer and CNS disorders. These provocative findings suggested that pharmacological inhibition of MAGL function may confer significant therapeutic benefits. In this study, we presented hybrid ligand and structure-based approaches to obtain a novel set of virtual leads as MAGL inhibitors. The constraints used in this study, were Glide score, binding free energy estimates and ADME properties to screen the ZINC database, containing approximately 21 million compounds. A total of seven virtual hits were obtained, which showed significant binding affinity towards MAGL protein. Ligand, ZINC24092691 was employed in complex form with the protein MAGL, for molecular dynamics simulation study, because of its excellent glide score, binding free energy and ADME properties. The RMSD of ZINC24092691 was observed to stay at 0.1 nm (1 Å) in most of the trajectories, which further confirmed its ability to inhibit the protein MAGL. The hits were then evaluated for their ability to inhibit human MAGL. The compound ZINC24092691 displayed the noteworthy inhibitory activity reducing MAGL activity to 21.15% at 100 nM concentration, with an IC50 value of 10 nM.

KEYWORDS:

Binding free energy estimates; E-Pharmacophore mapping; MAGL inhibition assay; Molecular docking; Molecular dynamics simulation; Monoacylglycerol lipase; Virtual screening

PMID:
25011912
DOI:
10.1016/j.bmcl.2014.06.029
[Indexed for MEDLINE]

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