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

Chemistry Central Journal

Salman Zafar²  M Iqbal Choudhary³  Kourosh Dalvandi¹  Uzma Mahmood¹  Zaheer Ul-Haq¹ 

[1] Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

[2] Department of Chemistry, Sarhad University of Science and Information Technology, Peshawar 25000, Pakistan

[3] Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah- 21412, Saudi Arabia

关键词: Molecular docking simulation;    Alzheimer’s disease;    Butyrylcholinesterase (BChE) inhibition;    Gibberella fujikuroi;    Macrophomina phaseolina;    Dihydrotestosterone (DHT);    Microbial transformation;   

Others  :  787830
DOI  :  10.1186/1752-153X-7-164

 received in 2013-05-06, accepted in 2013-08-29,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Zafar et al.; licensee Chemistry Central Ltd.

【 图 表 】

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