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. 2013 Oct 24:10:63.
doi: 10.1186/1742-4682-10-63.

Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines

Syed Sikander Azam  1 , Sumra Wajid Abbasi
Affiliations

Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines

Syed Sikander Azam et al. Theor Biol Med Model. .

Abstract

Background: N-Acetylserotonin O-methyltransferase (ASMT) is an enzyme which by converting nor-melatonin to melatonin catalyzes the final reaction in melatonin biosynthesis in tryptophan metabolism pathway. High Expression of ASMT gene is evident in PPTs. The presence of abnormally high levels of ASMT in pineal gland could serve as an indication of the existence of pineal parenchymal tumors (PPTs) in the brain (J Neuropathol Exp Neurol 65: 675-684, 2006). Different levels of melatonin are used as a trait marker for prescribing the mood disorders e.g. Seasonal affective disorder, bipolar disorder, or major depressive disorder. In addition, melatonin levels can also be used to calculate the severity of a patient's illness at a given point in time.

Methods: Seventy three melatoninergic inhibitors were docked with acetylserotonin-O-methyltransferase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking routines. Keeping this fact in view, critical evaluation of the performance of four different commonly used docking routines: AutoDock/Vina, GOLD, FlexX and FRED were performed. An evaluation criterion was based on the binding affinities/docking scores and experimental bioactivities.

Results and conclusion: Results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the compound selected as potent inhibitor is having minimum binding affinity, maximum GoldScore and minimum FlexX energy. The correlation value of r2 = 0. 66 may be useful in the selection of correct docked complexes based on the energy without having prior knowledge of the active site. This may lead to further understanding of structures, their reliability and Biomolecular activity especially in connection with bipolar disorders.

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Figures

Figure 1
Figure 1
ASMT catalyzed melatonin synthesis.
Figure 2
Figure 2
Percentages of docked poses for ASMT docked complexes obtained by the different docking routines.
Figure 3
Figure 3
Plot showing the correlation between the experimental bioactivities (PIC50) and a) binding affinities b) GOLD scores c) Chemgauss4 scores and d) binding energies.
Figure 4
Figure 4
Docked conformation of ASMT with top ranked ligands showing the interaction with the crucial residues in the active site cleft using: (a) AutoDock/Vina (b) GOLD (c) FlexX (d) FRED.
Figure 5
Figure 5
Docked poses: Binding mode of top ranked docked poses into ASMT binding cavity: (a) AutoDock/Vina (b) GOLD (c) FlexX (d) FRED For clarity, only interacting important residues are displayed in CPK style. The inhibitors were designed in licorice style, and part of the enzyme in the background was visualized in New Ribbon style using the VMD (Visual Molecular Dynamics) program.
See this image and copyright information in PMC

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