Abstract
The mobility of loops around the catalytic site of a protein remains crucial to its activity. Dynamics of the WPD-loop is an essential determinant of the catalytic activity of tyrosine-protein phosphatase zeta, an implicated protein in glioblastoma cells. The WPD-loop assumes a closed conformation upon substrate binding in order to position its catalytic aspartate to participate in catalysis. Herein, we explore the impact of NAZ2329, a recently identified allosteric inhibitor of tyrosine-protein phosphatase zeta, on the atomic flexibility of the WPD-loop. The druglikeness of NAZ2329 was assessed using the SwissADME online tool. The enzymatic complex was then subjected to conformational simulations using the AMBER molecular dynamics software. Structural analysis revealed that NAZ2329 induced an open conformation of the crucial WPD-loop, consequently impeding enzyme activity even upon substrate binding. Based on the molecular interactions between NAZ2329 and tyrosine-protein phosphatase zeta, a pharmacophore model was generated to exhibit the important functional moieties of NAZ2329. These findings provide an insightful molecular and structural mechanism in targeting tyrosine-protein phosphatase zeta as a therapeutic intervention for glioblastoma. We believe that this optimized pharmacophoric model will aid in the design of improved anti-tyrosine phosphatase agents, thus allowing for increased patient adherence.
Highlights
Glioblastoma is classi ed as the most aggressive and frequently diagnosed central nervous system malignancy, with an annual incidence of 100 000 new cases, globally.[1]
The WPD-loop, a vital catalytic site regulator, forms an outer cover to part of the allosteric site, indicating that the ligand that binds to this allosteric pocket would govern the dynamics of this loop
The lower root mean standard deviation (RMSD) of the NAZ2329-complex relative to the APO system suggest that the inhibitory activity of NAZ2329 possibly induced conformational dynamics that contributed to the system achieving stability at a lower RMSD
Summary
Glioblastoma is classi ed as the most aggressive and frequently diagnosed central nervous system malignancy, with an annual incidence of 100 000 new cases, globally.[1]. Adding to the complexity of the disease, glioblastoma is associated with poor prognosis and low survival rates. There have been numerous studies elucidating the development of new therapeutic approaches, including an article that investigated the receptor type tyrosine-protein phosphatase zeta (PTPRZ) as a target in glioblastoma cells.[5]. The PTPRZ enzyme plays a crucial role in regulating protein tyrosine phosphorylation, thereby leading to the survival of the glioblastoma cells and promoting the growth of tumors.[6]. Due to this mechanism of action, the PTPRZ enzyme is a crucial target in the design of efficient inhibitors of against glioblastoma.[3]
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