Unveiling the role of phytochemicals in autism spectrum disorder by employing network pharmacology and molecular dynamics simulation.

Autism Spectrum Disorder (ASD) comprises a myriad of disorders with vast pathologies, aetiologies, and involvement of genetic and environmental risk factors. Given the polygenic aspect of ASD, targeting several genes/proteins responsible for pathogenesis at once might prove advantageous in its remediation. Various phytochemicals have been proven to possess neuroprotective, anti-inflammatory, and antioxidant properties by alleviating symptoms and targeting a complex network of genes/proteins related to disease pathology. However, the effects of many of these phytochemicals on ASD are enigmatic, and their molecular targets and molecular mechanisms are still elusive. Here, we provide a comprehensive comparative study on the therapeutic potential of 6 phytochemicals viz. Cannabidiol, Crocetin, Epigallocatechin-3-gallate, Fisetin, Quercetin, and Resveratrol based on their neuroprotective properties in managing ASD. We aimed to identify and target a network of core proteins in the pathology of ASD via phytochemicals using network pharmacology, molecular docking, and simulation studies. The methodology includes screening genes/proteins implicated in ASD as targets of each phytochemical, followed by network construction using Protein-Protein Interactions, Gene Ontology, and enrichment analysis. The constructed network was further narrowed down to the hub genes in the network, followed by their spatio-temporal analysis, molecular docking, and molecular dynamics simulation. 6 core genes were obtained for ASD, 3 of which are directly involved in disease pathogenesis. The study provides a set of novel genes that phytochemicals can target to ameliorate and regulate ASD pathogenesis. Cannabidiol can inhibit ABCG2, MAOB, and PDE4B, Resveratrol can target ABCB1, and Quercetin can regulate AKR1C4 and XDH. This study demonstrated the potential of phytochemicals to target and regulate ABCG2, ABCB1, AKR1C4, MAOB, PDE4B, and XDH, which in turn modulate the dysfunctional network present in the ASD pathology and provide therapeutic potential in the management of ASD.