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

To identify potential inhibitors of Mcl-1, two molecular data sets were virtually screened and docked on to Mcl-1 using the AutoDock Vina program. 33 The molecular data sets include a lead-like subset and an FDA-approved subset. The lead-like data set was based on the standard lead-like of the ZINC database (version 12, September 29, 2014), 34 which contains 6,053,287 molecules from which a subset of 2,300,000 molecules were randomly selected. The leadlike library has been pre-filtered based on the properties of molecular weight between 250 and 350 g/mol, predicted partition constant (× LogP) #3.5, and number of rotatable bonds #7. The FDA-approved subset contained 1,790 FDAand internationally approved drugs and was kindly provided by Dominique Douguet from the Institut de Pharmacologie Moléculaire et Cellulaire. 35 To identify potential Mcl-1 inhibitors, we used multiple conformations of the protein. The multiple conformation comprised 20 NMR structures conformation of Mcl-1 (PDB ID 2MHS), 28 12 models obtained using NMA, and four models obtained using MD simulations. First, AutoDock calculation was performed on a representative structure of the NMR ensemble (model 1 of PDB ID 2MHS). Then, we picked the 1,000 ligands with the lowest binding energies and docked them on the multiple conformations sampled by NMR, NMA, and MD.