Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

Glantz-Gashai, Yitav; Meirson, Tomer; Reuveni, Eli; Samson, Abraham O

In Supplementary materials, Table S2 , the binding energies of all ligands and their standard deviation are provided. The standard deviation characterizes the variation from the average ligand binding energy to 20 NMR, four MD, and six NMA conformations. AutoDock Vina was applied once for each Mcl-1 protein conformation, but by sampling multiple conformations, the signal-to-noise ratio of true positives is expected to increase. Ligands with low standard deviation of binding energies usually have few rotatable bonds, are rigid, and sometimes symmetric. For example, dihydroartemisinin and artemeter are rigidified by the polycyclic skeleton, whereas carbofenotion contains a C2 axis of pseudosymmetry. Contrarily, ligands with high standard deviations are highly flexible. The standard deviation is an indicator of entropy, and the more conformations a ligand may adopt, the more receptor poses are possible. Often, drug candidates with low standard deviation are preferred as binding is confined, but not always.