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

Abstract

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.

A Small Molecule Inhibitor of VE-PTP Activates Tie2 in Schlemm's Canal Increasing Outflow Facility and Reducing Intraocular Pressure

“…AKB-9778 (razuprotafib; Aerpio Pharmaceuticals, Inc.) is a small molecule that activates Tie2 by inhibiting the intracellular catalytic domain of VE-PTP. [27][28][29] AKB-9778 has been in development as a novel subcutaneous therapy for the treatment of diabetic eye disease. [30][31][32] In two consecutive clinical trials in ocular normotensive human patients with diabetic eye disease, subcutaneous administration of AKB-9778 significantly lowered IOP.…”

Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study

“…The root-mean-square fluctuation (RMSF) values ( Figure 10 c) were used to evaluate the flexibility of the protein side chains, and the RMSF values of >0.35 nm were considered as high flexibility [ 33 ]. The RMSF values of the most residues in the 6 systems showed similar fluctuation, and the critical residues in all complexes exhibited low flexibility, illustrating that the key interactions of all compounds in the binding pocket might similar.…”

“…The pharmacophore features from the best pharmacophore model were extracted to use as a search query for the first-round screening. The QFIT parameters in the range of 0 to 100 were obtained to assess the matching degree of screened compounds with the pharmacophore features [ 33 ]. The compounds with a QFIT > 35 were then selected for the second-round screening of docking.…”

“…The equilibrium trajectory (the last 5 ns) of the MD simulations was extracted to calculate the binding free energy using the MM-PBSA method. The binding free energy was calculated as follows: in which G complex , G free-protein , and G free-ligand represent the free energy of protein–ligand complex, protein, and ligand, respectively [ 33 ].…”

An Insight of RuBisCO Evolution through a Multilevel Approach

“…In Figure 4, the eNMA shows the consensus fluctuations are highlighted and reveal a conserved pattern among species and RuBisCO forms (Figure 4a,b). The three isoforms show a greater fluctuation in the N-terminal domain spanning the amino acid residues (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) between the secondary elements αB and βC (Figure 4a), which are functionally relevant for RbcL. Likewise, RuBisCO form III presents greater fluctuation (≥3 Å) with respect to form I and II (Figure 4a,b).…”