Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation.

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.

• Authors: Jiasi Luan, Baichun Hu, Shizhun Wang, Haihan Liu, Shuaizhong Lu, Weixia Li, Xizhe Sun, Jiyue Shi, Jian Wang
• Journal: Physical chemistry chemical physics : PCCP (Phys Chem Chem Phys) Vol. 24 Issue 28 Pg. 17105-17115 (Jul 21 2022) ISSN: 1463-9084 [Electronic] England
• PMID: 35791860 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein

Topics

• Antineoplastic Agents (chemistry)
• Apoptosis
• Molecular Docking Simulation
• Proto-Oncogene Proteins c-bcl-2 (chemistry)
• bcl-X Protein (chemistry)