Myeloid Cell Leukemia 1 Inhibition: An in Silico Study Using Non-equilibrium 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 alpha-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. Model. 2017, 57, 1240]. As an important byproduct, this work constitutes hence one of the first and most challenging tryouts for the GAFF2 parameter set. Agreement with experimental measurements is found to be generally satisfactory, validating the GAFF2 parametrization of the ligands and foreseeing a possible role of FSDAM for industrial application in drug discovery.