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.

Unlabelled: Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson's disease. Recently, hMAO-B and hAR 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 hAR 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 ((E)-3-(3-Chlorophenyl)--(4-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) phenyl) acrylamide and ((E)-3-(3-Chlorophenyl)--(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 hAR targets respectively, and the stability of the studied complexes was confirmed during MD simulations. Also, the MEP maps of compounds and 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 , , 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.