Solid pseudopapillary neoplasia of the pancreas (SPN) is a rare pancreatic neoplasm that frequently harbors mutations in catenin β1 (CTNNB1, encoding β-catenin) as a part of its molecular pathogenesis. Mutations to CTNNB1 reported in SPN usually occur at the serine/threonine phosphorylation sites, including codons 33, 37 and 41, and the flanking residues of codon 33. On analysis of 3 cases of SPN, mutations to CTNNB1 were detected in codon 32 (D32A and D32Y). As this residue, aspartic acid, is not a direct phosphorylation site of the protein, molecular modeling tools were used to predict the influence of these mutations on the protein structure of β-catenin. A total of three MD simulations (wild-type, D32A, and D32Y) were performed to visualize the conformations of β-catenin under in vivo, aqueous-phase conditions at 37°C. In the wild-type protein, the secondary structure of residues P16-H28 remained helical; we therefore hypothesized that the helical structure of this protein fragment (residues M11-G50) was necessary for phosphorylation of S33 phosphorylation. The loss of the secondary structure in P16-H28 was observed in D32A, losing its helical structure and becoming a turn; however, in the D32Y mutant, the helical structure remained. The present demonstrated that structural changes in the mutated β-catenin protein at D32 could potentially explain the mechanism behind its defective phosphorylation in the pathogenesis of SPN.
The Thai banded tiger wasp (Vespa affinis) is a dangerous vespid species found in Southeast Asia, and its stings often result in fatalities due to the presence of lethal phospholipase A$$_{1}$$
1
, known as Vespapase or Ves a 1. Developing anti-venoms for Ves a 1 using chemical drugs, such as chemical drug guide, remains a challenging task. In this study, we screened 2056 drugs against the opening conformation of the venom using the ZINC 15 and e-Drug 3D databases. The binding free energy of the top five drug candidates complexed with Ves a 1 was calculated using 300-ns-MD trajectories. Our results revealed that voxilaprevir had a higher binding free energy at the catalytic sites than other drug candidates. Furthermore, the MD simulation results indicated that voxilaprevir formed stable conformations within the catalytic pocket. Consequently, voxilaprevir could act as a potent inhibitor, opening up avenues for the development of more effective anti-venom therapeutics for Ves a 1.
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