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Published on: December 21, 2019
Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation
Jiasi Luan1,2,3, Baichun Hu1,2,4, Shizhun Wang1,2,5
1Key Laboratory of Structure-Based Drug Design &Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China. jianwang@syphu.edu.cn.
Abstract:
The BCL-XL protein is among the most important members of the anti-apoptotic subfamily of the BCL-2 protein family, and is currently a promising new target for anti-tumor drug research. However, the BCL-XL/2 proteins have similar structures and functions, which could lead to undesirable side effects because of inhibitors that can bind to both BCL-XL and BCL-2. Therefore, it is crucial to expound on the structural basis of the selective mechanism towards BCL-XL/2 inhibition. In the current study, we employed hybrid computational methods including molecular docking and dynamics simulation, MM/GBSA energy calculation, alanine scanning mutagenesis and Hirshfeld surface analysis to comprehensively reveal the selectivity mechanism towards BCL-XL/2 from multiple perspectives, revealing the significant effects of the BCL-XL residues SER106 and LEU108 as well as the BCL-2 residue ASP103 on the inhibitory selectivity. Overall, our findings provide useful references for the rational design of BCL-XL/2 selective inhibitors with better affinity.
Insights
Researchers identified key protein residues (SER106, LEU108 in BCL-XL and ASP103 in BCL-2) crucial for selective anti-cancer drug targeting. This understanding aids in designing potent BCL-XL inhibitors with fewer side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The BCL-XL protein is a critical anti-apoptotic factor and a key target for anti-cancer drug development.
- Similar structures between BCL-XL and BCL-2 proteins pose challenges for developing selective inhibitors, potentially causing side effects.
Purpose of the Study:
- To elucidate the structural basis for selective inhibition of BCL-XL over BCL-2.
- To provide insights for the rational design of novel anti-cancer therapeutics targeting BCL-XL.
Main Methods:
- Hybrid computational approaches including molecular docking and dynamics simulations.
- MM/GBSA energy calculations, alanine scanning mutagenesis, and Hirshfeld surface analysis were employed.
- Multi-perspective analysis to comprehensively reveal the selectivity mechanism.
Main Results:
- Identified specific BCL-XL residues (SER106, LEU108) and a BCL-2 residue (ASP103) that significantly influence inhibitory selectivity.
- Detailed the structural interactions governing the differential binding of inhibitors.
Conclusions:
- The identified residues are critical determinants for achieving BCL-XL/2 selectivity.
- Findings offer valuable guidance for designing BCL-XL selective inhibitors with enhanced affinity and reduced off-target effects.
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