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Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone.

Zafar S, Choudhary MI, Dalvandi K, Mahmood U, Ul-Haq Z - Chem Cent J (2013)

Bottom Line: Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme.Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors.Metabolites 5-7 effectively inhibited the BChE activity.

View Article: PubMed Central - HTML - PubMed

Affiliation: H, E, J, Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi- 75270, Pakistan. salman.hej@gmail.com.

ABSTRACT

Background: Biotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites.

Results: Microbial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5α-androstan-3β,17β-diol (2), and 5β-androstan-3α,17β-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11α,17β-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11α-hydroxyandrost-4-en-3,17-dione (6), 11α-hydroxyandrost-1,4-dien-3,17-dione (7), 12β-hydroxyandrost-1,4-dien-3,17-dione (8), and 16α-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5-7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities.

Conclusion: Biotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5-7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer's disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced.

No MeSH data available.


Related in: MedlinePlus

Three Dimensional (3D) conformational differences of co-crystallized ligand (BCH) and its docked pose within binding site of 1p0p.
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Figure 4: Three Dimensional (3D) conformational differences of co-crystallized ligand (BCH) and its docked pose within binding site of 1p0p.

Mentions: Enzyme inhibition assay was carried out by using spectrophotometric method in 96-well plate. The experiments were conducted in triplicate. Substrate 1 showed a weak inhibition of the AChE. Therefore the substrate and its metabolites 2–7 were tested for AchE and BChE inhibitory activity. Interestingly all metabolites were found inactive against AChE. Metabolite 2 and 3 were also found to be inactive against the BChE, while metabolites 4–7 showed significant selective inhibition of BChE. Metabolites 5–7 were found to be the most active members (Table 2). Metabolites 2 and 3 lack a conjugated ketone system, while rest of the metabolites (i.e. 4–7) have a α,β-unsaturated ketone system. The activity might be attributed to the presence of a conjugated system which may help the molecule attain a suitable configuration for binding to the active site of BChE. Metabolites 4–7 have approximately the same structural features, with conjugated ketone functionalities and hydroxyl groups, except 5. Galanthamine was used as a standard inhibitor in the assay. Galanthamine is a potent cholinesterase inhibiting (approved by FDA in 2001) drug, which is used in clinical practices for the management of AD [28], Galanthamine is extensively used as standard to compare the potency of test compounds (IC50) [29] in biochemical assays. In docking study (Figure 4), galanthamine can bind to Trp 82 (anionic site) like active compounds 4-7, it means binding site for compounds and galanthamine is similar, therefore all compounds can be compared with standard in both potency and function.


Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone.

Zafar S, Choudhary MI, Dalvandi K, Mahmood U, Ul-Haq Z - Chem Cent J (2013)

Three Dimensional (3D) conformational differences of co-crystallized ligand (BCH) and its docked pose within binding site of 1p0p.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126177&req=5

Figure 4: Three Dimensional (3D) conformational differences of co-crystallized ligand (BCH) and its docked pose within binding site of 1p0p.
Mentions: Enzyme inhibition assay was carried out by using spectrophotometric method in 96-well plate. The experiments were conducted in triplicate. Substrate 1 showed a weak inhibition of the AChE. Therefore the substrate and its metabolites 2–7 were tested for AchE and BChE inhibitory activity. Interestingly all metabolites were found inactive against AChE. Metabolite 2 and 3 were also found to be inactive against the BChE, while metabolites 4–7 showed significant selective inhibition of BChE. Metabolites 5–7 were found to be the most active members (Table 2). Metabolites 2 and 3 lack a conjugated ketone system, while rest of the metabolites (i.e. 4–7) have a α,β-unsaturated ketone system. The activity might be attributed to the presence of a conjugated system which may help the molecule attain a suitable configuration for binding to the active site of BChE. Metabolites 4–7 have approximately the same structural features, with conjugated ketone functionalities and hydroxyl groups, except 5. Galanthamine was used as a standard inhibitor in the assay. Galanthamine is a potent cholinesterase inhibiting (approved by FDA in 2001) drug, which is used in clinical practices for the management of AD [28], Galanthamine is extensively used as standard to compare the potency of test compounds (IC50) [29] in biochemical assays. In docking study (Figure 4), galanthamine can bind to Trp 82 (anionic site) like active compounds 4-7, it means binding site for compounds and galanthamine is similar, therefore all compounds can be compared with standard in both potency and function.

Bottom Line: Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme.Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors.Metabolites 5-7 effectively inhibited the BChE activity.

View Article: PubMed Central - HTML - PubMed

Affiliation: H, E, J, Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi- 75270, Pakistan. salman.hej@gmail.com.

ABSTRACT

Background: Biotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites.

Results: Microbial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5α-androstan-3β,17β-diol (2), and 5β-androstan-3α,17β-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11α,17β-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11α-hydroxyandrost-4-en-3,17-dione (6), 11α-hydroxyandrost-1,4-dien-3,17-dione (7), 12β-hydroxyandrost-1,4-dien-3,17-dione (8), and 16α-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5-7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities.

Conclusion: Biotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5-7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer's disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced.

No MeSH data available.


Related in: MedlinePlus