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- Title
Study of Binding Thermodynamics in the Optimization of BH3 Mimetics.
- Authors
Zhang, Zhichao; Zhao, Yan; Song, Ting; Liu, Yubo; Li, Xiangqian; Su, Pengchen; Xie, Shenghui
- 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 n m, which is a 104-fold improvement compared with 1. Analysis of the enthalpy and − TΔ S 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.
- Subjects
B cells; CANCER treatment; CALORIMETRY; ENTHALPY; LEUKEMIA; ISOTHERMAL titration calorimetry; CELL death
- Publication
Chemical Biology & Drug Design, 2013, Vol 82, Issue 4, p394
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12161