Supporting material of: Multistage Molecular Simulations, Design, Synthesis, and Anticonvulsant Evaluation of 2-(Isoindolin-2-yl) Esters of Aromatic Amino Acids Targeting GABAA Receptors via π–π Stacking

This is the supporting data of the manuscript entitled: "Multistage Molecular Simulations, Design, Synthesis, and Anticonvulsant Evaluation of 2-(Isoindolin-2-yl) Esters of Aromatic Amino Acids Targeting GABAA Receptors via π–π Stacking".
The deposited data includes:

INDEX

1 General Methods 3
2 Synthesis and Characterization 4
2.1 Synthesis of methyl (S)-(1H-indol-3-yl)-2-(isoindolin-2-yl) propanoate (1) 4
2.2 Synthesis of methyl (S)-3-(4-hydroxyphenyl)-2-(isoindolin-2-yl) propanoate (2) 4
3 Biological assay 6
4 ADMET Profiling of Selected Schiff Base Derivatives 7
5 Plots, Statistical Analysis and Visualizations 13
5.1 Descriptive Statistics 13
6 Structure-Activity Relationship (SAR) 21
6.1 Aromatic Preference and Workflow 21
6.1.1 Library Design: Sixteen Isoindoline Esters Derived from Natural Amino Acids 21
6.1.2 Grouping Compounds by Side Chain Type 21
6.1.3 Summary of Core Properties 22
6.2 Physicochemical and ADMET Filtering 23
6.2.1 Physicochemical Space and CNS Compatibility 23
6.2.2 Hydrogen Bonding Profiles 24
6.2.3 ADMET Prediction Results 24
6.2.4 Conclusion of Filtering Step 24
6.3 Molecular Docking & π–π Interaction Profile 25
6.3.1 Docking Score Comparison and Prioritization 25
6.3.2 Interaction Mapping and Pose Analysis 25
6.3.3 Receptor Environment and Aromatic Selectivity 25
6.3.4 Conclusion 25
6.4 Binding Energy Landscape (Metadynamics) 26
6.4.1 Objective and Rationale 26
6.4.2 Simulation Protocol 26
6.4.3 Free Energy Profiles 27
6.4.4 Interpretation of Binding Modes 27
6.4.5 Summary 27
6.5 Receptor-Specific Interpretation 28
6.5.1 GABAA Receptor Binding Site Characteristics 28
6.5.2 Implications for Ligand Design 28
6.5.3 Mimicry of Classical Benzodiazepines 28
6.5.4 Conclusion 29
6.6 Comparative SAR Insights and Outliers 29
6.6.1 Ranking and Performance Clustering 29
6.6.2 Outlier Analysis 29
6.6.3 Non-Aromatic Class Performance 30
6.6.4 SAR Summary Table Reference 30
6.7 Design Implications and Next-Generation Analogs 30
6.7.1 Key Design Principles 30
6.7.2 Recommended Modifications 30
6.7.3 Broader Application 31
6.7.4 Conclusion 31
6.8 SAR Conclusion 31
7 NMR and MS Specters 33
8 References 39