Exploring the effect of inhibitor AKB-9778 on VE-PTP by molecular docking and molecular dynamics simulation.

Diabetic macular edema, also known as diabetic eye disease, is mainly caused by the overexpression of vascular endothelial protein tyrosine phosphatase (VE-PTP) at hypoxia/ischemic. AKB-9778 is a known VE-PTP inhibitor that can effectively interact with the active site of VE-PTP to inhibit the activity of VE-PTP. However, the binding pattern of VE-PTP with AKB-9778 and the dynamic implications of AKB-9778 on VE-PTP system at the molecular level are poorly understood. Through molecular docking, it was found that the AKB-9778 was docked well in the binding pocket of VE-PTP by the interactions of hydrogen bond and Van der Waals. Furthermore, after molecular dynamic simulations on VE-PTP system and VE-PTP AKB-9778 system, a series of postdynamic analyses found that the flexibility and conformation of the active site undergone an obvious transition after VE-PTP binding with AKB-9778. Moreover, by constructing the RIN, it was found that the different interactions in the active site were the detailed reasons for the conformational differences between these two systems. Thus, the finding here might provide a deeper understanding of AKB-9778 as VE-PTP Inhibitor.

Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation.

Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome (LS), is an autosomal dominant inherited multisystemic disorder. Most patients involve mutation in SHP2 encoded by tyrosine-protein phosphatase non-receptor type 11 (PTPN11) gene. Studies have shown that NSML-associated Y279C mutation exhibited the reduced phosphatase activity, leading to loss-of-function (LOF) of SHP2. However, the effect of the Y279C mutation on the SHP2 at the molecular level is unclear. In this study, molecular dynamics simulations of SHP2 wild-type (SHP2WT) and Y279C mutant (SHP2Y279C) were performed to investigate the structural differences in proteins after Y279C mutation and to find out the reason for loss-of-function of SHP2. Through a series of post-dynamic analyses, it was found that the protein occupied a smaller phase space after Y279C mutation, showing reduced flexibility. Specifically, due to the mutation of Y279C, the secondary structures of these two regions (residues Lys70-Ala72 and Gly462-Arg465) were significantly transformed from Turn to α-helix and ß-strand. Furthermore, by calculating the residue interaction network, hydrogen bond occupancy and binding free energy, it was further revealed that the conformational differences between SHP2WT and SHP2Y279C systems were mainly caused by the differences in the interaction between Arg465-Phe469, Ile463-Gly467, Cys279-Lys70, Cys459-Ala72, Gly464-Phe71, Phe71-Ile463, Ile463-Ala505 and Arg465-Glu361. Consequently, this finding is expected to provide a new insight into the reason for loss-of-function of SHP2 caused by Y279C mutation.Communicated by Ramaswamy H. Sarma.