A Virtual screening campaign for beta-amyloid aggregation inhibitors.

BARRERA GUISASOLA, EXEQUIEL E.; PORFIDO JORGE

Workshop; EMBO Workshop: Advances and Challenges in Biomolecular Simulations.; 2021

Smallsoluble β-amyloid oligomers present cytotoxic properties that highlycorrelate with symptoms severity in Alzheimer?s Disease1.Employing Aβ42 dimers as macromolecular targets a ~ 200,000 compoundsubset of the ZINC database was included in a Virtual Screening (VS)campaign. First,we simulated multiple β-amyloid dimerization and maturation eventswith the SIRAH coarse-grained force field2.Multi-microsecond simulations were clustered to select threerepresentative dimeric structures. Using a blind docking strategywith AutoDock Vina3,compounds were docked into atomic structures of the modeled targets,selecting them according to their affinity values and bindingselectivity towards aggregation hot-spots, previously calculated withHADDOCK4.Using the boiled-egg model to predict both brain and intestinalpermeation, ten compounds with these characteristics passed to thenext VS stage. Here, all-atom molecular dynamics simulations wereemployed to assess the complex stability and capacity of thecompounds to disrupt monomer-monomer interactions. Next, werecalculated binding affinities using a MM/GBSA approach. Threecompounds binding with the highest affinities and disrupting keymonomer-monomer interactions were selected to test their capacityusing invivoexperiments.Here, we employed a C. elegans strain that expresses Aβ42 in itsbody wall muscle cells as a β-amyloid toxicity model. This stage ofthe study is now in progress, and micromolar concentrations of thecompounds are expected to prevent the progressive paralysis of thenematodes exerted by β-amyloid aggregation. Experimental resultswill be available by the workshop?s poster presentation date.p { margin-bottom: 0.1in; direction: ltr; font-variant: normal; color: #000000; letter-spacing: normal; line-height: 115%; text-align: justify; page-break-inside: auto; orphans: 2; widows: 2; text-decoration: none; page-break-before: auto; page-break-after: auto }p.western { font-family: "Calibri", serif; font-size: 10pt; so-language: en-US; font-style: normal; font-weight: normal }p.cjk { font-family: "Calibri"; font-size: 10pt; so-language: en-US; font-style: normal; font-weight: normal }p.ctl { font-family: "Calibri"; font-size: 10pt; so-language: ar-SA; font-style: normal; font-weight: normal }a:link { color: #000000; text-decoration: underline }