Molecular docking/dynamics simulations, MEP analysis, bioisosteric replacement and ADME/T prediction for identification of dual targets inhibitors of Parkinson's disease with novel scaffold

Abstract

Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson's disease. Recently, hMAO-B and hA_2AR Dual-targets inhibitory potential of a novel series of Phenylxanthine derivatives has been established in experimental findings. Hence, the current study examines the interactions between 38 compounds of this series with hMAO-B and hA_2AR targets using different molecular modeling techniques to investigate the binding mode and stability of the formed complexes. A molecular docking study revealed that the compounds L24 ((E)-3-(3-Chlorophenyl)-N-(4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and L32 ((E)-3-(3-Chlorophenyl)-N-(3-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)acrylamide) had a high affinity (S-score: -10.160 and -7.344 kcal/mol) with the pocket of hMAO-B and hA_2AR targets respectively, and the stability of the studied complexes was confirmed during MD simulations. Also, the MEP maps of compounds 24 and 32 were used to identify the nucleophilic and electrophilic attack regions. Moreover, the bioisosteric replacement approach was successfully applied to design two new analogs of each compound with similar biological activities and low energy scores. Furthermore, ADME-T and Drug-likeness results revealed the promising pharmacokinetic properties and oral bioavailability of these compounds. Thus, compounds L24, L32, and their analogs can undergo further analysis and optimization in order to design new lead compounds with higher efficacy toward Parkinson's disease.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-023-00139-3.

Keywords: ADME-T; Bioisosteric replacement; MEP maps; Molecular docking/dynamics; Parkinson’s disease; Phenylxanthine derivatives.

Scheme 1

General protocol of calculation steps, as well as the methods used in the study

Fig. 1

Validation of molecular docking protocol by re-docking; a SAF into the MOA-B, b XAC into the hA_2AAR

Fig. 2

2D Visualization of the binding modes of the best compounds L9, L10, L24, and SAF inside the active site of hMAO-B target

Fig. 3

2D Visualization of the binding modes of the best compounds L5, L14, L32, and XAC inside the active site of hA_2AAR target

Fig. 4

The compound 24; docked (pink) well into the binding site of hMAO-B and has the highest dock score; there is also a clear difference between the final ligand pose and the docking pose (green) after a molecular dynamics (MD) (pink) simulation in NVT

Fig. 5

The compound 32; docked (yellow) well into the binding site of hA_2AR and has the highest dock score; there is also a clear difference between the final ligand pose and the docking pose (red) after a molecular dynamics (MD) (yellow) simulation in NVT

Fig. 6

Results of molecular dynamics simulation of hMAO-B-L24 docked complex. a Eigenvalue, b variance (red color indicates individual variances and green color indicates cumulative variances), c elastic network (darker grey regions indicate stiffer regions) of the complex, d co-variance map (correlated (red), uncorrelated (white) or anti-correlated (blue) motions), e B-Factor mobility

Fig. 7

Results of molecular dynamics simulation of the hA_2AR-L32 docked complex. a eigenvalue, b variance (red color indicates individual variances and green color indicates cumulative variances), c elastic network (darker grey regions indicate stiffer regions) of the complex, d co-variance map (correlated (red), uncorrelated (white) or anti-correlated (blue) motions), e B-Factor mobility

Fig. 8

ESP-mapped van der Waals surfaces (kcal/mol) using a color scale ranging from red (negative ESP) through white (neutral ESP) to blue (positive ESP). The blue regions are prone to nucleophilic attack, and the red regions are sites for electrophilic attack. The grid spacings were set to 0.2 Bohr, and the van der Waals surface denotes the isosurface of ρ = 0.001*e/Bohr³ (a.u). The bold numbers in the bottom right-hand corner are the positive ESP variance (PV), negative ESP variance (NV), positive surface area (A +), and negative surface area (A −) whose units are (Kcal/mol)², Ų, respectively