Molecular Docking, Molecular Dynamics Simulation, DFT, and ADMET Prediction of...

Parkinson's Disease (PD) is the most common neurodegenerative disease worldwide. Monoamine Oxidase B (MAO-B), which is associated with oxidative stress, is a suitable target for PD treatment. This study aimed to explore the inhibitory potential of 3- carbonyl-3-hydroxyl-isoindolin-1-one compounds against MAO-B through various in-silico studies.

A library of 279 isoindolin-1-one compounds was screened against the MAO-B protein using molecular docking with the GLIDE module of Schrödinger suite 2022.4. The top two candidates were further evaluated using 500 ns molecular dynamics simulations (MDS) with the Desmond module, MM-GBSA binding free energy calculations with Prime, ADMET analysis with the QikProp module, and density functional theory (DFT) calculations with the Jaguar module of Schrödinger suite 2022.4.

Ligands 90 and 173 exhibited the highest docking scores of -12.088 kcal/mol and -12.085 kcal/mol, respectively, and formed hydrogen bonds with MAO-B residues. 500 ns MDS studies confirmed the stability of the docked poses of ligands 90 and 173 with RMSD values below 2 Å and stable hydrogen bonding interactions with the protein. MMGBSA analysis indicated that the MAO-B complexes of ligands 90 and 173 displayed significantly lower binding free energy values of -85.465 kcal/mol and -78.840 kcal/mol, respectively. ADMET predictions of ligands 90 and 173 were observed to be within the satisfactory range. DFT analysis of ligands 90 and 173 depicted high chemical reactivity and low kinetic stability.

Ligands 90 and 173 were identified as promising MAO-B inhibitors with high binding affinities, acceptable pharmacokinetic profiles, and high chemical reactivity, highlighting their potential as lead compounds for developing therapeutic agents against PD.