Screening ApoE4-Targeting Compounds Using Glide Docking

To identify the best candidates in the ChemBridge library that target ApoE4, we used the Glide docking protocol^{7 (link),8 (link),10 (link)}. Briefly, the pocket identified as the DNA-binding region of ApoE4 was placed within a docking grid box. The full ChemBridge structural library of ~780,000 compounds were prepared using the Ligand Preparation Wizard from the Schrodinger Small Molecule Drug Discovery Suite. Prepared ligands were initially screened under the HTVS protocol in the Glide docking package. For high-stringency (phase II) docking, we employed high-precision mode within the Glide docking package. Highest-stringency (phase III) screening used the Molecular Mechanics Generalized Born Solvent Accessible (MM-GBSA) protocol from Schrodinger Prime module. All three-dimensional results were analyzed in Maestro and BIOVIA Discovery Studio visualizers.