Current Proteomics - Volume 21, Issue 4, 2024

The molecular properties of TLSs in pancreatic cancer are still not well comprehended. This research delved into the molecular properties of intratumoral TLSs in pancreatic cancer through the exploration of multi-omics data.

Seven key genes were identified through Cox regression analysis and random survival forest analysis from a total of 5908 genes related to TLSs. These genes were utilized to construct a prognosis model, which was subsequently validated in two independent cohorts. Additionally, the study investigated the molecular features of different populations of TLSs from multiple perspectives. The model’ s forecasting accuracy was verified by analyzing nomogram and decision curves, taking into account the patients’ clinical traits.

The analysis of immune cell infiltration showed a notably greater presence of Macrophage M0 cells in the group at high risk than in the low-risk group. The pathway enrichment analysis demonstrated the activation among common cancer-related pathways, including ECM receptor interaction, pathways in cancer, and focal adhesion, in the high-risk group. Additionally, the methylation study revealed notable disparities in DNA methylation between two TLS groups across four regions: TSS200, 5’ UTR, 1stExon, and Body. A variety of notably distinct sites were linked with PVT1. Furthermore, by constructing a competing endogenous RNA network, several mRNAs and lncRNAs were identified that compete for the binding of hsa-mir-221.

Overall, this research sheds light on the molecular properties of TLSs across various pancreatic cancer stages and suggests possible focal points for the treatment of pancreatic cancer.

A pivotal impetus has led to the development of numerous small molecules to develop therapeutic strategies for type 2 diabetes. Novel heterocyclic derivatives are now available with expansive pharmacological activity designed specifically to activate Glucokinase (GK) in the body. This target is of particular significance in antidiabetic drug design since it is a newly validated target. Individuals with type 2 diabetes are unable to maintain blood glucose homeostasis due to impaired glucokinase function. The novel approach to managing type 2 diabetes relies on utilizing heterocyclic derivatives to activate the GK enzyme, also known as a metabolic enzyme.

In this research endeavor, the primary objective was to improve drug delivery while minimizing adverse effects by using molecules that activate glucokinase.

There are 53,000 compounds included in Maybridge's online repository, which has been subjected to rigorous scrutiny. Eight two compounds that encompass the specific oxadiazole core were selectively extracted from this extensive collection. ChemBioDraw Ultra was used for structural drawing, and AutoDock Vina 1.5.6 was used to perform docking analysis. For the online prediction of log P, the SwissADME algorithm was employed. A PKCSM software program was used to predict toxicity for leading compounds.

Among all of the compounds, AD80 and AD27 displayed the highest affinity for GK receptors. These compounds, by adhering to Lipinski’s Rule of Five, exhibited good absorption and excretion profiles through the gastrointestinal (GI) tract. Lipinski’s Rule of Five refers to physicochemical properties that favor good oral bioavailability, and these specifications are zero to five hydrogen bond donors, zero to ten hydrogen bond acceptors, molecular weight below 500, and log P no more than five. These criteria ensure that the compounds of the invention have acceptable solubility and permeability, which are vital prerequisites when given orally, to be absorbed via the gastrointestinal wall, metabolized, and found in the urine. Therefore, the chance of drug candidates exhibiting favorable pharmacokinetic characteristics is increased, enhancing their chances of being developed for oral administration. In comparison with standard drugs Dorzagliatin as a glucokinase activator (GKA) and MRK (co-crystallized ligand), these compounds exhibit no skin sensitization, AMES toxicity, or hepatotoxicity.

The recently designed lead molecules exhibit an improved pharmacokinetic profile, enhanced binding affinity, and minimal toxicity based on the computational study, potentially making them suitable candidates for further optimization as glucokinase activators.