Computational model for lipid binding regions in phospholipase (Ves a 1) from Vespa venom.

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[Formula: see text], 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.

In silico prediction of Antifungal compounds from Natural sources towards Lanosterol 14-alpha demethylase (CYP51) using Molecular docking and Molecular dynamic simulation.

An increase in the occurrence of fungal infections throughout the world, as well as the rise of novel fungal strains and antifungal resistance to commercially available drugs, suggests that new therapeutic choices for fungal infections are needed. The purpose of this research was to find new antifungal candidates or leads of secondary metabolites derived from natural sources that could effectively inhibit the enzymatic activity of Candida albicans lanosterol 14-alpha demethylase (CYP51) while also having good pharmacokinetics. In silico prediction of the drug-likeness, chemo-informatics and enzyme inhibition indicate that the 46 compounds derived from fungi, sponges, plants, bacteria and algae sources have a high novelty to meet all five requirements of Lipinski's rules and impede enzymatic function. Among the 15 candidate molecules with strong binding affinity to CYP51 investigated by molecular docking simulation, didymellamide A-E compounds demonstrated the strongest binding energy against the target protein at -11.14, -11.46, -11.98, -11.98, and -11.50 kcal/mol, respectively. Didymellamide molecules bind to comparable active pocket sites of antifungal ketoconazole and itraconazole medicines by hydrogen bonds forming to Tyr132, Ser378, Met508, His377 and Ser507, and hydrophobic interactions with HEM601 molecule. The stability of the CYP51-ligand complexes was further investigated using molecular dynamics simulations that took into account different geometric features and computed binding free energy. Using the pkCSM ADMET descriptors tool, several pharmacokinetic characteristics and the toxicity of candidate compounds were assessed. The findings of this study revealed that didymellamides could be a promising inhibitor against these CYP51 protein. However, there is still a need for further in vivo and in vitro studies to support these findings.

Molecular dynamic simulation of mutated ß-catenin in solid pseudopapillary neoplasia of the pancreas.

Solid pseudopapillary neoplasia of the pancreas (SPN) is a rare pancreatic neoplasm that frequently harbors mutations in catenin ß1 (CTNNB1, encoding ß-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 ß-catenin. A total of three MD simulations (wild-type, D32A, and D32Y) were performed to visualize the conformations of ß-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 ß-catenin protein at D32 could potentially explain the mechanism behind its defective phosphorylation in the pathogenesis of SPN.