Myeloid cell leukemia 1 inhibition: An in silico study using nonequilibrium fast double annihilation technology

In this work, we compute, by means of a non-equilibrium alchemical technique (fast switching double annihilation methods, FSDAMs), the dissociation free energy for five recently discovered micromolar to sub-nanomolar inhibitors of the Myeloid cell leukemia 1 protein, a key regulator in cell survival and death, providing valuable clues in the chemical-physical determinants of Mcl-1 inhibition. Using the same methodology, we attempt the calculation of the dissociation free energy of the BH3 domain from PUMA protein, binding Mcl-1 in the α-helical state. The synthetic ligands have been parametrized using the recently released GAFF2 general force field [ http://ambermd.org ] by means of the automated assignment tool PrimaDORAC [ Procacci , P. J. Chem. Inf.