CHRNA5 D398N mutation in addiction: Pathogenic insights and therapeutic discovery

Background: Drug addiction is a significant public health issue, with genetic components playing a role in predisposing a person to susceptibility. Objective: the current study planned to investigate the pathogenic potential of the CHRNA5 D398N (rs16969968) mutation and computationally identify structurally optimized aripiprazole analogs capable of selectively binding the mutant protein. Methods: PolyPhen-2 and AlphaMissense were used to assess the pathogenic impact of the D398N (rs16969968) mutation in CHRNA5. SwissSimilarity was employed to identify aripiprazole-like structural analogs for therapeutic screening. The chemical structures of selected analogs were drawn and optimized using ChemDraw. SwissADME was used to evaluate pharmacokinetic properties, including drug-likeness and absorption parameters. Molecular docking was performed to estimate the binding affinity of candidate ligands toward the mutant CHRNA5 protein, while Density Functional Theory (DFT) analysis was conducted to determine their electronic, reactive, and electrostatic properties for final lead selection. Results: Functional prediction tools, including PolyPhen-2 and Alpha Missense, predict the mutation to be pathogenic with high scores predicting deleterious effects. Structural modeling with AlphaFold showed conformational changes in the mutant CHRNA5 protein, especially at the active site, validated with structural alignment. For therapeutic potential, 20 structurally similar aripiprazole ligands were identified through Swiss Similarity. Molecular docking indicated ligand 12 and ligand 4 had the highest binding affinity for mutant protein (?3.034 and ?2.774 kcal/mol, respectively). PyMOL visualization indicated ligand-receptor interactions. ADMET analysis predicted good pharmacokinetics: Ligand 12 indicated high gastrointestinal absorption and CYP non-inhibition, while ligand 4 was a non-P-gp substrate with good solubility. DFT analysis indicated ligand 4 was the most polar, while ligand 12 was the most chemically reactive. Conclusion: These findings imply the D398N mutation predisposes to addiction susceptibility and that ligand 12 holds promise as a therapeutic target due to its high binding affinity and good pharmacological profiles.