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

Monoamine oxidase B and Adenosine A2A receptors are used as key targets for Parkinson’s disease. Recently, hMAO-B and hA 2A R 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 2A R 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 2A R 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.