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

Abstract

BackgroundBiotransformation 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.ResultsMicrobial 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.ConclusionBiotransformation 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.

Fungal transformation of androsta-1,4-diene-3,17-dione by Aspergillus brasiliensis

“…The absorbance at 3408 cm −1 , confirmed the existance of a hydroxyl group. Melting point, 13 C-NMR and 1 H-NMR spectral data, assignments and chemical shifts for this compound were in agreement with those which have been reported by Zafar et al in 2013 for 12β-hydroxyandrost-1,4-dien-3,17-dione [ 19 ].…”

“…This compound which is significant and specific inhibitor of butyrylcholinesterase (BChE), in comparison to standard drug, galanthamine. 12β-hydroxyandrost-1,4-diene-3,17-dione (IV) was also another hydroxylated steroid which has been obtained from DHT biotransformation by G. fujikuroi [ 19 ]. Although hydroxylation of steroidal substrates is common by filamentous fungi, hydroxylation at C-12 position is relatively rare [ 6 ].…”

Anticancer potential of β-sitosterol and oleanolic acid as through inhibition of human estrogenic 17beta-hydroxysteroid dehydrogenase type-1 based on an in silico approach

“…The redocking step has been widely implemented for efficient molecular docking calculations. 19,20 The analysis was carried out on the TES coordinates as a reference for the cocrystals. The coordinates showed that the position of TES is in the pocket of the HSD17B1 enzyme (Fig.…”

“…Molecular docking provides good calculation efficiency for inhibitor coordination on the enzyme active site. 19,20 Meanwhile, the MD simulation offers a comprehensive analysis of the interaction between an inhibitor and the targeted protein during the simulation time. 17,21 The evaluation proceeds by several considerations, such as grid-score 20 and binding free energy, 22 aiming to see the binding affinity of inhibitor to HSD17B1.…”

The catalytic activity of mycelial fungi towards 7‐oxo‐DHEA – an endogenous derivative of steroidal hormone dehydroepiandrosterone

“…This system has been associated with a number of cognitive functions, including memory and emotional processing. To date, a number of in vitro studies on inhibitory effects of various steroidal molecules have been carried out, and some of them have been identified as weak or strong inhibitors of these cholinesterases (Richmond et al ., 2013; Zafar et al ., 2013; Yusop et al ., 2020).…”