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

Jiasi Luan, Baichun Hu, Shizhun Wang, Haihan Liu, Shuaizhong Lu, Weixia Li, Xizhe Sun, Jiyue Shi, Jian Wang

Physical chemistry chemical physics : PCCP 2022 Jul 21

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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.

Citation

Jiasi Luan, Baichun Hu, Shizhun Wang, Haihan Liu, Shuaizhong Lu, Weixia Li, Xizhe Sun, Jiyue Shi, Jian Wang. Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation. Physical chemistry chemical physics : PCCP. 2022 Jul 21;24(28):17105-17115