Targeting SHANK1 with <i>Withania Somnifera</i> Phytochemicals: A Molecular Dynamics Approach for Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder linked to synaptic impairment. SHANK1, a postsynaptic scaffolding protein, is crucial for organizing excitatory synapses and its disruption is associated with the pathogenesis of ASD. Therefore, targeting SHANK1 represents a promising therapeutic strategy. Given this, SHANK1 was selected by convergent evidence from ASD-curated genetics, synaptic network centrality within an ASD-restricted PPI module, and structural feasibility of a resolved SHANK1 domain for small-molecule interrogation. A computational drug discovery strategy was employed to identify natural modulators derived from Withania somnifera (W. somnifera), a medicinal plant recognized for its neuroprotective properties. A total of 141 bioactive compounds from W. somniferawere evaluated against the SHANK1 protein, subsequently undergoing ADMET profiling, molecular dynamics simulations (MDS), and MM/PBSA binding free energy assessments. MM/PBSA estimated binding free energies (mean ± SD) were for Risperidone −18.97 (± 5.45) kcal/mol; CID 73145 −16.16 (± 3.91) kcal/mol; CID 162882388 −15.69 (± 3.78) kcal/mol; CID 163045002 −15.44 (± 5.25) kcal/mol; and CID 163071136 −19.58 (± 5.88) kcal/mol indicating stable interactions with essential SHANK1 residues. MDS confirmed the conformational stability of the selected complexes over 200 ns, as shown by consistent RMSD, RMSF, radius of gyration, hydrogen bonding patterns and beneficial principal component trajectories. The analysis of the free energy landscape indicated energetically favorable binding conformations, while the MM/PBSA results showed substantial binding energies for all candidate ligands. Pharmacokinetic and toxicity assessments revealed that the selected compounds exhibited high oral bioavailability, minimal toxicity and favorable drug-like properties. This study identifies promising phytochemicals from W. somniferaas potential modulators of SHANK1, facilitating further experimental validation and therapeutic development for ASD.