Computational Prediction of Hot Spots and Binding Site of Inhibitor NSC23766 on Rac1 Binding With Tiam1

• Published in: Frontiers in chemistry Vol. 8; p. 625437
• Main Authors: Zheng, Chunwen, Wu, Xiaodong, Zeng, Ruijie, Lin, Lirui, Xu, Liyan, Li, Enmin, Dong, Geng
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 02.02.2021
• Subjects: binding free energy; Chemistry; MD simulation; molecular docking; NSC23766; Rac1; Tiam1; MD simulation; Tiam1; molecular docking; Rac1; NSC23766; binding free energy
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2020.625437

Rac1 is a small signaling protein, which belongs to the Rho subfamily of Ras superfamily. It is activated by binding GTP and inactivated by exchanging GDP for GTP. The ability of nucleotide exchange depends on guanine nucleotide exchange factors (GEFs) family proteins. T-lymphoma invasion and metastasis factor 1 (Tiam1) is a member of GEFs. Rac1 participates in multiple signaling pathways and regulates various cellular events by interacting with GEFs. Particularly, it is involved in the development and progression of various kinds of tumors. In this paper, we have studied the detailed interaction between Rac1 and Tiam1. Seven residues on Rac1 are predicted to be important for the interaction with Tiam1, i.e. E31, Y32, D38, N39, Y64, D65 and W56. All these residues are located on the switch 1 and 2 domains which are the interface between Rac1 and Tiam1, except W56. In addition, we analyzed how inhibitor NSC23766 interacts with Rac1. Our docking results show that NSC23766 binds to the same region as Tiam1. Several residues, i.e. F37, D38, N39, W56, Y64, L67, L70 and S71, contribute much to binding free energy. These findings are very useful for the structure-based design of inhibitors toward Rac1.