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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

Metabolites of biotransformation of DHT (1) with Gibberella fujikuroi.
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Figure 3: Metabolites of biotransformation of DHT (1) with Gibberella fujikuroi.

Mentions: This is the first report of microbial transformation of DHT (1) (Figure 1), (C19H30O2) with M. phaseolina and G. fujikuroi. Fermentation of compound 1 with M. phaseolina for 6 days led to the formation of two known metabolites 2 and 3 (Figure 2), while 7 days fermentation of 1 with G. fujikuroi yielded six known metabolites 4–9 (Figure 3). Structure elucidation of all metabolites is presented below.


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)

Metabolites of biotransformation of DHT (1) with Gibberella fujikuroi.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Metabolites of biotransformation of DHT (1) with Gibberella fujikuroi.
Mentions: This is the first report of microbial transformation of DHT (1) (Figure 1), (C19H30O2) with M. phaseolina and G. fujikuroi. Fermentation of compound 1 with M. phaseolina for 6 days led to the formation of two known metabolites 2 and 3 (Figure 2), while 7 days fermentation of 1 with G. fujikuroi yielded six known metabolites 4–9 (Figure 3). Structure elucidation of all metabolites is presented below.

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