Deciphering the Anti-Autism Potential of Withania somnifera Phytochemicals Targeting SLC6A4 Through Computational Approaches

Autism is a complex developmental condition caused by variations in brain function. Individuals with autism spectrum disorder (ASD) frequently exhibit difficulties in behavior, communication, social interactions, and learning. Although the exact cause of ASD is unknown, research suggests that a combination of genetic, non-genetic, and environmental factors may contribute to its onset. This study investigates the therapeutic potential of bioactive compounds derived from Withania somnifera ( W. somnifera ), focusing on the genetic aspect of ASD via modulation of the sodium-dependent serotonin transporter gene ( SLC6A4 ). Structure-based virtual screening was performed on W. somnifera -derived compounds using AutoDock Vina, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and validation through 200 ns molecular dynamics simulations (MDS). Also, MDS confirmed the stability of the compounds interacting with SLC6A4 , followed by molecular mechanics Poisson–Boltzmann surface area (MMPBSA)-based free energy calculations. Three candidates, compound ID (CID) 5280343, CID 9798666, and CID 99148, showed higher binding affinities (−9.7, −9.6, and −9.5 kcal/mol) than the control drug paroxetine (−9.3 kcal/mol). All three compounds satisfied ADMET criteria and showed stable interactions throughout the simulations, yielding favorable MMPBSA outcomes. These analyses point to CID 5280343, CID 9798666, and CID 99148 as potential candidates for developing ASD therapies. Additional experimental studies are required to investigate and validate their therapeutic potential.