Study On HSV-mediated Aβ Aggregation Mechanism And Virtual Screening Of Anti-aggregation Drugs

Alzheimer’s Disease（AD）,the most common cause of dementia,is recognized as the heterogeneous disease with diverse pathophysiologic mechanisms.The deposition of Aβin the brain is involved in the early pathogenesis of AD,which results in the formation of senile plaques that cause oxidative damage,neuronal cell death and eventual decline in cognitive function.The molecular mechanisms involved in the physiopathology are still unclear.In clinical,Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset.The development of new drugs is urgently needed.Herpes virus（HSV）is a neurotropic human pathogen.It has been found that the protective innate immune response of Aβhas been indicated as a risk factor for AD due to the rapid amyloidosis.In order to obtain molecular-level insights into the protective and pathogenic roles of Aβ,the binding mode between Aβand herpes virus glycoprotein were theoretically studied via molecular docking,MD simulation and MM/PBSA methods.The analyses of the results showed that both Aβmonomers and fiber can stably bind to the envelop g D on the surface of HSV-1 by the intermolecular hydrogen bonds and van der Waals interactions.The observed ofβ-sheets and salt bridge appearance,indicating a tendency to aggregate,which was conducive to fibrosis transformation.Therefore,HSV can be captured by Aβand participate in AD-related amyloidosis.Virtual drug screening and Molecular dynamics（MD）simulation are widely used in the development and screening of new drugs.To quickly screen new compounds that is able to bind to Aβand inhibit conformational aggregation,a series of elegant computational biology approaches were used for analysis.In this study,the potential inhibitors of Aβwere screened out according to molecular docking.Furthermore,MD and MM/PBSA analysis affirmed the stability and binding pattern of the docked complexes.The inhibitory effects of small molecules,DB09031 and DB11164,on Aβaggregation were discovered and analyzed.DB09031 bound to the central hydrophobic region and C-terminal residues of Aβ_1-42by hydrophobic interaction.The results indicated that DB09031 stabilizes conformations of Aβ_1-42,facilitating formation of helices,thereby inhibiting aggregation of Aβ.DB11164 interfered with the salt bridge between chains through hydrophobic interaction with the key aggregation tendency area of Aβfibril,which caused the Aβfibril to depolymerize.In this study,we investigated the effects of Aβaggregation induced by HSV infection and explored potential immunoprotective mechanisms.Two small molecules potentially inhibiting Aβaggregation were discovered through virtual screening.Our work provided a theoretical basis for subsequent research design and screening of new drugs,which can be used as the direction for AD treatment.