Integrated Virtual Screening Approaches to Identify Novel N- Substituted Heterocyclic Compounds as MAPK Inhibitors for Neuro Inflammation.

INTRODUCTION

The Mitogen-Activated Protein Kinase (MAPK) is an intricately linked signaling cascade that frequently contributes to drug resistance in neurodegenerative diseases. This study presents an integrated approach combining in silico molecular docking, ADMET-based screening, and evaluation to identify novel N-substituted heterocyclic compounds as MAPK inhibitors for neuroinflammation.

METHODS

The molecular docking of the designed 135 nitrogen-substituted 5-, 6-, and 7- membered derivatives was carried out using Flare GUI software, docked into the MAPK (p38, ERK, JNK) binding site with PDB code 3LN1. The interaction was evaluated based on the reranked score comparison between the designed derivatives and the co-crystallized ligand. Trametinib was used as the reference, and 8 selected compounds were evaluated for their ADMET profiling using Swiss ADME, Molinspiration, OSIRIS, and Protox II. The molecules were filtered for their drug-like properties.

RESULTS

The docking results showed that more than 6% of the designed compounds displayed a good binding score compared with the reference Trametinib. The three targets used for screening are P38-alpha MAP kinase (2BAL), mitogen-activated protein kinase 1 ERK (3I5Z), and JNK-interacting protein 1 (7NYK). A maximum binding score of -8 kcal/mol was found for P38-alpha MAP kinase (2BAL).

DISCUSSION: ADMET screening gave 13 selected compounds that displayed affirmative pharmacokinetic and pharmacodynamic profiles, paving the way for many new drugs for development.

CONCLUSION

There is a large scope for the optimization of the core, suggesting that the screened 8 molecules might be promising targets as inhibitors of P38-alpha MAP kinase in the MAPK pathway and are feasible to be synthesized.