Department of Chemistry , University of Florence , Via Lastruccia No. 3 , Sesto Fiorentino I-50019 , Italy.
J Chem Theory Comput. 2018 Jul 10;14(7):3890-3902. doi: 10.1021/acs.jctc.8b00305. Epub 2018 Jun 20.
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.
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.
在这项工作中，我们通过非平衡热力学技术（快速切换双湮灭方法，FSDAMs）计算了最近发现的五种微摩尔至亚纳摩尔的髓系白血病 1 蛋白抑制剂的离解自由能，髓系白血病 1 蛋白是细胞存活和死亡的关键调节因子，为 Mcl-1 抑制的化学物理决定因素提供了有价值的线索。使用相同的方法，我们尝试计算 PUMA 蛋白 BH3 结构域与 Mcl-1 结合的α螺旋状态的离解自由能。通过自动分配工具 PrimaDORAC [Procacci，P. J. Chem. Inf. Model. 2017, 57, 1240]，使用最近发布的 GAFF2 通用力场对合成配体进行了参数化。作为一个重要的副产品，这项工作构成了 GAFF2 参数集的首次和最具挑战性的尝试之一。实验测量结果表明，结果通常令人满意，验证了配体的 GAFF2 参数化，并预见了 FSDAM 在药物发现工业应用中的可能作用。
