The X-ray structure of the PWWP domain of ZMYND11 (PDB ID: 4N4I)14 (link) was prepared with PrepWizard (Schrodinger, New York) using the standard protocol, including the addition of hydrogens, the assignment of bond order, assessment of the correct protonation states, and a restrained minimization using the OPLS-AA 2005 force field. Receptor grids were calculated at the centroid of the trimethyllysine (M3L) with the option to dock ligands of similar size.
A lead-like library of ~2 million compounds was prepared with LigPrep (Schrodinger, New York). The resulting library was then docked using the virtual screening workflow using Glide HTVS in the first stage, followed by Glide SP in the second stage (Schrodinger, New York). After removing the compounds with a docking score worse than −7 kcal/mol and that do not contain a tertiary amine, the remaining 18k compounds were docked with Glide XP. Next, compounds with a docking score better than −8 kcal/mol or with a score better than −6 kcal/mol and two hydrogen bonds with nearby residues (R317, F311, H313, N316, W319, H314, S340) were selected for visual inspection. This step selected 431 compounds, which were rescored with the GBSA method (AMBER 12, UCSF). The compounds were clustered and the ones with GBSA > −15 kcal/mol were removed. Finally, after a visual inspection, 40 compounds were selected to be purchased.
A lead-like library of ~2 million compounds was prepared with LigPrep (Schrodinger, New York). The resulting library was then docked using the virtual screening workflow using Glide HTVS in the first stage, followed by Glide SP in the second stage (Schrodinger, New York). After removing the compounds with a docking score worse than −7 kcal/mol and that do not contain a tertiary amine, the remaining 18k compounds were docked with Glide XP. Next, compounds with a docking score better than −8 kcal/mol or with a score better than −6 kcal/mol and two hydrogen bonds with nearby residues (R317, F311, H313, N316, W319, H314, S340) were selected for visual inspection. This step selected 431 compounds, which were rescored with the GBSA method (AMBER 12, UCSF). The compounds were clustered and the ones with GBSA > −15 kcal/mol were removed. Finally, after a visual inspection, 40 compounds were selected to be purchased.
