Identification of anti-Parkinson's Disease Lead Compounds from Aspergillus ochraceus Targeting Adenosin Receptors A2A

Abstract

Two novel alkaloids compounds together with fifteen know metabolites were identified from Aspergillus ochraceus. The stereochemistry features of the new molecules were determined via HRESIMS, NMR, ECD, and XRD analyses. Amongst these, compounds two compounds exhibited potential efficacy as anti-Parkinson's disease with the EC₅₀ values of 2.30 and 2.45 μM, respectively. ADMET prediction showed that these compounds owned favorable drug-like characteristics and safe toxicity scores towards CNS drugs. Virtual screening analyses manifested that the compounds exhibited not only robust and reliable interactions to adenosine receptors A_2A , but also higher binding selectivity to A_2A receptors than to A₁ and A₃ receptors. Molecular dynamics simulation demonstrated the reliability of molecular docking results and the stability of the complexes obtained with the novel compounds and A_2A receptors in natural environments. It is the first time that anti-PD lead compounds have been identified from Aspergillus ochraceus and targeting adenosine A_2A receptors.

Keywords: Aspergillus ochraceus; Parkinson's disease; adenosine receptors; alkaloids; drug discovery; virtual screening.

Figure 1

Structures of compounds 1–17 from Aspergillus ochraceus.

Figure 2

Key 2D NMR correlations of compounds 7 and 17.

Figure 3

Experimental ECD spectra of 7 and 17, and calculated ECD spectra of 19R‐7, 19S‐7, and 12R‐17.

Figure 4

X‐ray ORTEP drawing of 7 and 17.

Figure 5

Effects on SH‐SY5Y cells and MPP⁺ insult SH‐SY5Y cells viabilities of compounds 14 and 15 were evaluated using Levodopa (LD) as a positive control in vitro. Both values of CC₅₀ and EC₅₀ were calculated as mean values with standard deviations (n=3, P<0.05).

Figure 6

Left: the change of RMSD of backbone atoms in molecular dynamics simulation; Right: the change of RMSF of amino acid residues in molecular dynamics simulation.

Figure 7

Residue interaction histograms of non‐bond interactions of 14‐A_2AR complex. A: Residues with favorable interactions; B: Residues with unfavorable interactions; C: Residues with hydrogen bond interactions; D: Residues with hydrophobic interactions.

Figure 8

Visual graphic interactions of molecular docking between 14 and A_2AR. Left: the whole drawing of 14‐A_2AR; Right: the amplified drawing of 14 docking in pocket sites of A_2AR (The above: 3D graphic; The Below: 2D graphic).

Figure 9

A) MS spectrum of methanol extract of A. ochraceus cultivated in PDA‐Control; B) MS spectrum of methanol extract of A. ochraceus cultivated in PDA‐Test.