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 test the validity of our in silico assay, we virtually docked several ligands known to bind to Mcl-1 and compared their predicted binding energy with their experimental binding constants. These ligands included the small molecules 36 The ligands were virtually docked to the multiple Mcl-1 conformations calculated herein using AutoDock Vina. 33 The ligands displayed predicted attractive (negative) binding energies in the following order: -4.97 Kcal/mol (3WIX), -4.86 Kcal/mol (4HW3), -4.82 Kcal/mol (4ZBI), -4.74 Kcal/mol (4ZBF), -2.95 Kcal/mol (5FDO), -0.5 Kcal/mol (5FDR), and repulsive (positive) binding energy +16.6 Kcal/mol (ABT-737). Remarkably, the ligands were ranked in accordance with their experimental binding constants, namely, ,1 nM (3WIX), ~10 nM (4HW3), ~10 nM (4ZBI), ~10 nM (4ZBF), ~100 nM (5FDO), ~100 nM (5FDR), and no binding (ABT-737). The small molecule, ABT-737, which does not bind to Mcl-1, provided a positive repulsive energy. Assuming that the positive binding energy was an error, the Pearson's correlation coefficient of the predicted and observed binding is 0.90. Thus, in a small data set, the predictive capacity of our in silico assay was confirmed, and we set out to test it in large data sets. Table 1 lists the top 10 lead-like molecules (see Supplementary materials, Figure S2 ) that bind to each Mcl-1 conformation sampled by NMR, NMA, and MD. The top 10 lead-like molecules are ranked according to their average binding energy. Interestingly, the three conformations (NMR, NMA, and MD) give diverse top 10 ranked compounds.