Integrating transcriptomic data with a novel drug efficacy prediction model for TCM active compound discovery.

Identifying the active natural compounds remains a challenge for drug discovery, and new algorithms need to be developed to predict active ingredients from complex natural products. Here, we proposed Meta-DEP, a Meta-paths-based Drug Efficacy Prediction based on drug-protein-disease heterogeneity network, where Meta-paths contain all the shortest paths between drug targets and disease-related proteins in the network and drug efficacy is measured by a predictive score according to drug disease network proximity. Experiments show that Meta-DEP performs better than traditional network topology analysis on drug-disease interaction prediction task.

Discovery of novel diaryl substituted isoquinolin-1(2H)-one derivatives as hypoxia-inducible factor-1 signaling inhibitors for the treatment of rheumatoid arthritis.

Since synovial hypoxic microenvironment significantly promotes the pathological progress of rheumatoid arthritis (RA), hypoxia-inducible factor 1 (HIF-1) has been emerged as a promising target for the development of novel therapeutic agents for RA treatment. In this study, we designed and synthesized a series of diaryl substituted isoquinolin-1(2H)-one derivatives as HIF-1 signaling inhibitors using scaffold-hopping strategy. By modifying the substituents on N-atom and 6-position of isoquinolin-1-one, we discovered compound 17q with the most potent activities against HIF-1 (IC = 0.

Apolipoprotein E (ApoE) orchestrates adipose tissue inflammation and metabolic disorders through NLRP3 inflammasome.

Obesity is a metabolic disorder characterized by the hypertrophy expansion of adipose tissue, resulting in dysregulated energy metabolism, and accompanied by chronic low-grade inflammation. Adipose tissue macrophages (ATMs), a principal component of inflammation, respond to microenvironment signals and modulate adipose tissue remodeling and metabolic processes situation-specific. However, the mechanisms governing how the organism maintains equilibrium between its chronic inflammation and metabolism still need to be understood.

Novel deep learning-based transcriptome data analysis for drug-drug interaction prediction with an application in diabetes.

Background: Drug-drug interaction (DDI) is a serious public health issue. The L1000 database of the LINCS project has collected millions of genome-wide expressions induced by 20,000 small molecular compounds on 72 cell lines. Whether this unified and comprehensive transcriptome data resource can be used to build a better DDI prediction model is still unclear.

Discovery of an Inhibitor for the TREK-1 Channel Targeting an Intermediate Transition State of Channel Gating.

Modulators can be designed to stabilize the inactive and active states of ion channels, but whether intermediate (IM) states of channel gating are druggable remains underexplored. In this study, using molecular dynamics simulations of the TWIK-related potassium channel 1 (TREK-1) channel, a two-pore domain potassium channel, we captured an IM state during the transition from the down (inactive) state to the up (active-like) state. The IM state contained a druggable allosteric pocket that was not present in the down or up state.

The Mechanism by Which Luteolin Disrupts the Cytoplasmic Membrane of Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most versatile human pathogens. Luteolin (LUT) has anti-MRSA activity by disrupting the MRSA cytoplasmic membrane. However, the mechanism by which luteolin disrupts the membrane remains unclear.

An allosteric ligand-binding site in the extracellular cap of K2P channels.

Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are thus potential drug targets for treating diseases. Here, we identify N-(4-cholorphenyl)-N-(2-(3,4-dihydrosioquinolin-2(1H)-yl)-2-oxoethyl)methanesulfonamide (TKDC) as an inhibitor of the TREK subfamily, including TREK-1, TREK-2 and TRAAK channels. Using TKDC as a chemical probe, a study combining computations, mutagenesis and electrophysiology reveals a K2P allosteric ligand-binding site located in the extracellular cap of the channels.

Characterizing the interactions of two lipid modifications with lipid rafts: farnesyl anchors vs. palmitoyl anchors.

Farnesyl (Far) and palmitoyl (Pal) anchors play important roles in the traffic of many lipidated proteins. Herein, we show the distinctive interactions and influences of the two lipid modifications on lipid rafts (LRs) and non-raft-like membranes using molecular dynamics simulations. Palmitoyl anchors behave in a more ordered fashion, pack tighter with the lipids of LRs and diffuse at a slower rate than farnesyl anchors in LRs.

Two-quartet G-quadruplexes formed by DNA sequences containing four contiguous GG runs.

The DNA sequence containing four contiguous GG runs (G2NxG2NyG2NzG2, G2 sequence) has the potential to form a two-quartet G-quadruplex. However, the prevalence, structure, and function of G2 sequences have not been well-studied. Here, bioinformatics analysis reveals the abundance of G2 sequences in the human genome and their enrichment in promoter regions.