Selectivity mechanism of BCL-XL/2 inhibition through investigation

• Published in: Physical chemistry chemical physics : PCCP 2022-07, Vol.24 (28), p.1715-17115
• Main Authors: Luan, Jiasi, Hu, Baichun, Wang, Shizhun, Liu, Haihan, Lu, Shuaizhong, Li, Weixia, Sun, Xizhe, Shi, Jiyue, Wang, Jian
• Format: Article
• ISSN: 1463-9076; 1463-9084
• DOI: 10.1039/d2cp01755e

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. Comprehensive in silico investigation reveals that the BCL-XL residues SER106 and LEU108 and BCL-2 residues ASP103, TYR108, and TYR202 significantly affect selectivity by forming interactions with different molecular scaffolds.