Computational investigation of unsaturated ketone derivatives as MAO-B inhibitors by using QSAR, ADME/Tox, molecular docking, and molecular dynamics simulations

Abstract

Unsaturated ketone derivatives are known as monoamine oxidase B (MAO-B) inhibitors, a potential drug target for Parkinson's disease. Here, molecular modeling studies, including 2D-QSAR, ADMET prediction, molecular docking, and MD simulation, were performed on a new series of MAO-B inhibitors. The objective is to identify new MAO-B inhibitors with high inhibitory efficacy. The developed 2D-QSAR model was based on the descriptors of MOE software. The most appropriate model, using the partial least squares regression (PLS regression) method, yielded 0.88 for the determination coefficient (r²), 0.28 for the root-mean-square error (RMSE), and 0.2 for the mean absolute error (MAE). The predictive capacity of the generated model was evaluated by internal and external validations, which gave the Q² and R²_test values of 0.81 and 0.71, respectively. The ability of a compound to be orally active was determined using the drug-likeness and ADMET prediction. The results indicate that most of the compounds have moderate pharmacokinetic characteristics without any side effects. Furthermore, the affinity of the ligands (unsaturated ketone derivatives) to the MAO-B receptor was determined using molecular docking. The top conformers were then subjected to MD simulation. This research may pave the way for the development of novel unsaturated ketone derivatives capable of inhibiting the MAO-B enzyme.

Keywords: MAO-B inhibitors; Parkinson’s disease; ligand-based drug design; structure-based drug design.

Figure 1

Mechanism of interaction of monoamine oxidase-B (MAO-B) inhibitors. AD = dopamine, L-Dopa = levodopa, AADC = aromatic L-amino acid decarboxylase, 3-OMD = 3-O-methyldopa, COMT = catechol-O-methyltransferase, TH = tyrosine hydroxylase, and DOPAC = 3, 4-dihydroxyphenylacetic acid.

Figure 2

Chemical structures of chalcones (1), α, β-unsaturated ester derivatives (2), and α, β-unsaturated amide derivatives (3).

Figure 3

Core substructure of unsaturated ketone derivatives.

Figure 4

Plot of predicted and observed activity. The blue dots denote internal validation (LOO), whereas the orange dots represent external validation.

Figure 5

Contribution of descriptors in the generated 2D-QSAR model.

Figure 6

Applicability domain of the generated 2D-QSAR model. The blue dots represent the training set compounds and the red dots represent the test set compounds.

Figure 7

Correlation between the binding free energy values and the pIC50 values.

Figure 8

Docking analysis of compound 10b. (a) 2D view of binding site interactions, (b) 3D view of the binding conformation.

Figure 9

Docking analysis of compound 10e. (a) 2D view of binding site interactions, (b) 3D view of the binding conformation.

Figure 10

Molecular dynamics simulations of the 10b_2BK3 complex. (a) represents the RMSD plot, (b) represents the RMSF plot, (c) represents the Rg plot, and (d) represents the superposition of the final complex structure after MD simulation of 20 ns (green color) and initial complex structures before MD simulation (blue color).