title: Study of binding thermodynamics in the optimization of BH3 mimetics.
abstract: The use of small molecule B-cell lymphoma 2 homology domain 3 mimetics to neutralize the B-cell lymphoma 2 protein is an attractive strategy for cancer treatment due to its ability to cause targeted cell apoptosis. We have previously reported the design and optimization of a series of B-cell lymphoma 2 homology domain 3-mimetics, called compounds 1-6. In this study, we evaluated the optimization of B-cell lymphoma 2 homology domain 3-mimetics from a thermodynamic perspective. Understanding the thermodynamic parameters of B-cell lymphoma 2 homology domain 3-mimetics plays a critical role in the development of B-cell lymphoma 2 small-molecule inhibitors. The thermodynamic parameters for the interactions of these compounds with the myeloid cell leukemia sequence 1 protein were obtained using isothermal titration calorimetry. Owing to compounds 1-6 overcoming enthalpy-entropy compensation, the affinities of them improved gradually. Toward binding to the myeloid cell leukemia sequence 1 protein, compound 6 was deemed optimal with an obtained Kd value of 238 nm, which is a 10(4) -fold improvement compared with 1. Analysis of the enthalpy and -TΔS efficiencies showed that ligand efficiencies with respect to molecular size are correlated with the enthalpic efficiencies. Notably, an enthalpy gain of 4.65 kcal/mol identified that an additional hydrogen bond is formed by 2 with myeloid cell leukemia sequence 1 compared with compound 1. For the first time, hydrogen bonding between a small-molecule inhibitor of B-cell lymphoma 2 was demonstrated experimentally.
authors: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116012, China.
authors: Zhichao
authors: Z
authors: Zhang
authors: Yan
authors: Y
authors: Zhao
authors: Ting
authors: T
authors: Song
authors: Yubo
authors: Y
authors: Liu
authors: Xiangqian
authors: X
authors: Li
authors: Pengchen
authors: P
authors: Su
authors: Shenghui
authors: S
authors: Xie
mesh_terms: D002151:Calorimetry; D006801:Humans; D018716:Molecular Mimicry; D013816:Thermodynamics
keywords: Gibbs free energy; enthalpy; entropy; hydrogen bond; isothermal titration calorimetry; thermodynamics