Molecular design of hydroxamic acid-based derivatives as urease inhibitors of Helicobacter pylori.

Helicobacter pylori is the main causative agent of gastric cancer, especially non-cardiac gastric cancers. This bacterium relies on urease producing much ammonia to colonize the host. Herein, the study provides valuable insights into structural patterns driving urease inhibition for high-activity molecules designed via exploring known inhibitors. Firstly, an ensemble model was devised to predict the inhibitory activity of novel compounds in an automated workflow (R2 = 0.761) that combines four machine learning approaches. The dataset was characterized in terms of chemical space, including molecular scaffolds, clustering analysis, distribution for physicochemical properties, and activity cliffs. Through these analyses, the hydroxamic acid group and the benzene ring responsible for distinct activity were highlighted. Activity cliff pairs uncovered substituents of the benzene ring on hydroxamic acid derivatives are key structures for substantial activity enhancement. Moreover, 11 hydroxamic acid derivatives were designed, named mol1-11. Results of molecular dynamic simulations showed that the mol9 exhibited stabilization of the active site flap's closed conformation and are expected to be promising drug candidates for Helicobacter pylori infection and further in vitro, in vivo, and clinical trials to demonstrate in future.

Revealing the Effect of the Molecular Weight Distribution on the Chain Diffusion and Crystallization Process under a Branched Trimodal Polyethylene System.

With the increasing demand for high-end materials, trimodal polyethylene (PE) has become a research hotspot in recent years due to its superior performance compared with bimodal PE. By means of molecular dynamics (MD) simulations, we aim to expound the effect of the molecular weight distribution (MWD) on the mechanism of nucleation and crystallization of trimodal PE. The crystallization rate is faster when short-chain branching is distributed on a single backbone compared to that on two backbones. In addition, as the content of high molecular weight backbone decreases, the time required for nucleation decreases, but the crystallization rate slows down. This is because low molecular weight backbones undergo intra-chain nucleation and crystallize earlier due to the high diffusion capacity, which leads to entanglement that prevents the movement of medium or high molecular weight backbones. Furthermore, crystallized short backbones hinder the movement and crystallization of other backbones. What is more, a small increase in the high molecular weight branched backbone of trimodal PE can make the crystallinity greater than that of bimodal PE, but when the content of high molecular weight backbone is too high, the crystallinity decreases instead, because the contribution of short and medium backbones to high crystallinity is greater than that of long backbones.

Molecular insight into binding affinities and blockade effects of selected flavonoid compounds on the PD-1/PD-L1 pathway.

This study investigated the binding mechanisms of the flavonoids apigenin (Api), kaempferol (Kmp), and quercetin (Que) to the PD-L1 dimer using a combination of molecular modeling and experimental techniques. The binding free energy results demonstrated that the flavonoids could tightly bind to the PD-L1 dimer, with the binding abilities following the trend Que > Kmp > Api. Key residues Ile54, Tyr56, Met115, Ala121, and Tyr123 were identified as important for binding. The flavonoids primarily bind to the C-, F-, and G-sheet domains. The spontaneous formation of the complex systems was mainly driven by hydrophobic forces. Dynamic cross-correlation matrix and secondary structure analyses further indicated that the studied flavonoids could stably interact with the binding sites. ELISA results showed that the flavonoids could effectively block PD-1/PD-L1 interactions, although the inhibitory activity of Api was weaker. Therefore, flavonols might be more effective inhibitors compared to flavones. The findings of this study are expected to contribute to the development of novel flavonoids targeting the PD-1/PD-L1 pathway.