Limits...
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

Docking conformation of galanthamine (generated by MOE docking software) properly accommodated into the binding cavity of BChE enzyme and developed hydrogen bond interaction with catalytic residue GLU197 at 2.61 Å.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126177&req=5

Figure 5: Docking conformation of galanthamine (generated by MOE docking software) properly accommodated into the binding cavity of BChE enzyme and developed hydrogen bond interaction with catalytic residue GLU197 at 2.61 Å.

Mentions: Molecular docking studies demonstrated that all compounds were well accommodated inside the binding pocket of BChE. Due to the larger binding pocket of BChE, bulkier compounds like DHT derivatives are easily placed themselves inside the binding gorge. The best selected dock pose of galanthamine, used as standard inhibitor, exhibited hydrogen bond interaction with catalytic triad residue Glu197 at 2.16 Å with all possible conserved interactions within 5.0 Å (Figure 5). From the analysis of various inhibitors (1–7), we conducted that due to lack of carbonyl moiety and a double bond in ring “A”, compounds 1–3 were not able to productively engage with the enzyme, the outcome was well correlated with experimental results. Both functional groups actively participated in the inhibition of BChE activity and are involved in the interactions with key residues, as shown in the Figure 6. The presence of both the functional groups in compounds seems to be prerequisite to inhibit the BChE activity. From this postulation, compounds 5–7 were identified as active inhibitors. Depth analysis exhibited the role of double bond in assisting the compound to attain a favorable orientation towards the binding residue TRP82 which is involved in the inhibition and thus participate in π-π interaction between the DHT derivatives and BChE. In active site, two most important residues of BChE (TYR128 and TYR332) are frequently involved in hydrogen bonding and play an important inhibitory role. By docking experiment, SER198, GLU197, HIS438, TYR128, TYR332, PRO285, PHE329, GLY115, GLY439 and TRP82 were identified as key residues, located within the binding pocket of BChE.


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)

Docking conformation of galanthamine (generated by MOE docking software) properly accommodated into the binding cavity of BChE enzyme and developed hydrogen bond interaction with catalytic residue GLU197 at 2.61 Å.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Docking conformation of galanthamine (generated by MOE docking software) properly accommodated into the binding cavity of BChE enzyme and developed hydrogen bond interaction with catalytic residue GLU197 at 2.61 Å.
Mentions: Molecular docking studies demonstrated that all compounds were well accommodated inside the binding pocket of BChE. Due to the larger binding pocket of BChE, bulkier compounds like DHT derivatives are easily placed themselves inside the binding gorge. The best selected dock pose of galanthamine, used as standard inhibitor, exhibited hydrogen bond interaction with catalytic triad residue Glu197 at 2.16 Å with all possible conserved interactions within 5.0 Å (Figure 5). From the analysis of various inhibitors (1–7), we conducted that due to lack of carbonyl moiety and a double bond in ring “A”, compounds 1–3 were not able to productively engage with the enzyme, the outcome was well correlated with experimental results. Both functional groups actively participated in the inhibition of BChE activity and are involved in the interactions with key residues, as shown in the Figure 6. The presence of both the functional groups in compounds seems to be prerequisite to inhibit the BChE activity. From this postulation, compounds 5–7 were identified as active inhibitors. Depth analysis exhibited the role of double bond in assisting the compound to attain a favorable orientation towards the binding residue TRP82 which is involved in the inhibition and thus participate in π-π interaction between the DHT derivatives and BChE. In active site, two most important residues of BChE (TYR128 and TYR332) are frequently involved in hydrogen bonding and play an important inhibitory role. By docking experiment, SER198, GLU197, HIS438, TYR128, TYR332, PRO285, PHE329, GLY115, GLY439 and TRP82 were identified as key residues, located within the binding pocket of BChE.

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