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

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

Pistagremic acid, a novel β-secretase enzyme (BACE1) inhibitor from <i>Pistacia integerrima</i> Stewart

<div><p>A new triterpenic compound named pistagremic acid (PA) was once again isolated from <i>Pistacia</i><i>integerrima</i>. The β-secretase inhibition study was carried out. Compound PA was found significantly active against β-secretase enzyme (BACE1) with IC₅₀ value of 350 ± 2 nM in comparison to the standard inhibitors [Asn670, Sta671, Val672]-amyloid-β/A4 precursor protein 770 fragment 662–675 (IC₅₀ = 290.71 ± 1 nM). The selectivity of this compound was also evaluated against the acetylcholinesterase and butyrylcholinesterase enzymes. Interestingly compound PA was found to be inactive against them and showed selectivity towards β-secretase enzyme (BACE1).</p></div