Computation-Enabled Structure-Based Discovery of Potent Binders for Small-Molecule Aptamers.

Aptamers, functional nucleic acids recognized for their high target-binding affinity and specificity, have been extensively employed in biosensors, diagnostics, and therapeutics. Conventional screening methods apply evolutionary pressure to optimize affinity, while counter-selections are used to minimize off-target binding and improve specificity. However, aptamer specificity characterization remains limited to target analogs and experimental controls.

Aminopeptidase N-Activated Self-immolative Hydrogen Sulfide Donor for Inflammatory Response-Specific Wound Healing.

Hydrogen sulfide (HS) plays crucial inflammatory modulating roles, representing a promising candidate for anti-inflammatory therapies. However, current HS delivery approaches lack sufficient specificity against inflammatory response. Herein, regarding the overexpressed aminopeptidase N (APN) at the inflammation sites, an APN-activated self-immolative carbonyl sulfide (COS)/HS donor (AlaCOS) was developed for inflammatory response-specific HS delivery.

Modular preparation of biphenyl triazoles via click chemistry as non-competitive hyaluronidase inhibitors.

Hyaluronidase is a promising target in drug discovery, given its overexpression in a range of physiological and pathological processes, including tumor migration, skin aging, sagging, and wrinkling, as well as inflammation and bacterial infections. In this study, to identify novel hyaluronidase inhibitors, we applied click chemistry for the modular synthesis of 370 triazoles in 96-well plates, starting with biphenyl azide. Utilizing an optimized turbidimetric screening assay in microplates, we identified Fmoc-containing triazoles 5 and 6, as well as quinoline-containing triazoles 15 and 16, as highly effective hyaluronidase inhibitors.

Engineered assemblies from isomeric pentapeptides augment dry eye treatment.

Changing positions of amino acid residues in the peptide sequence alters the peptide' s assembly behaviors, affording various nanostructures. However, it remains elusive that how subtle changes in the peptide sequence influence the in vivo bioactivity of peptide-based nanocarriers, further impacting the efficacy of the encapsulated drugs. We report here a class of isomeric pentapeptide amphiphiles that associate into filaments with different dimensions, which were further used as carriers of Diquafosol tetrasodium (DQS), for the treatment of dry eye disease.

Molecular dynamics simulations reveal the inhibition mechanism of Cdc42 by RhoGDI1.

Cell division control protein 42 homolog (Cdc42), which controls a variety of cellular functions including rearrangements of the cell cytoskeleton, cell differentiation and proliferation, is a potential cancer therapeutic target. As an endogenous negative regulator of Cdc42, the Rho GDP dissociation inhibitor 1 (RhoGDI1) can prevent the GDP/GTP exchange of Cdc42 to maintain Cdc42 into an inactive state. To investigate the inhibition mechanism of Cdc42 through RhoGDI1 at the atomic level, we performed molecular dynamics (MD) simulations.

Advances in the development of Rho GTPase inhibitors.

Rho guanosine triphosphatases (Rho GTPases), as members of the Ras superfamily, are GDP/GTP binding proteins that behave as molecular switches for the transduction of signals from external stimuli. Rho GTPases play essential roles in a number of cellular processes including cell cycle, cell polarity as well as cell migration. The dysregulations of Rho GTPases are related with various diseases, especially with cancers.

Activation Mechanism of RhoA Caused by Constitutively Activating Mutations G14V and Q63L.

RhoA, a member of Rho GTPases, regulates myriad cellular processes. Abnormal expression of RhoA has been implicated in various diseases, including cancers, developmental disorders and bacterial infections. RhoA mutations G14V and Q63L have been reported to constitutively activate RhoA.

Validation of catalytic site residues of Ubiquitin Specific Protease 2 (USP2) by molecular dynamic simulation and novel kinetics assay for rational drug design.

Post-translational modifications of proteins such as protein ubiquitination are crucial for regulating conformation, stability and localization of the modified protein. Ubiquitin-specific protease 2 (USP2), a multifunctional cysteine protease is reported to be a key regulator of ubiquitylation events in numerous oncogenic proteins e.g.

Discovery of oridonin as a novel agonist for BRS-3.

Background: Bombesin Receptor Subtype-3 (BRS-3, Bombesin-like receptor, BB) is an orphan G-protein coupled receptor (GPCR). Recent studies have shown that BRS-3 played a vital role in glucose regulation, insulin secretion, and energy homeostasis. Therefore, discovering more novel exogenous ligands with diverse structures for BRS-3 will be of great importance for target validation and drug development.

Molecular dynamics simulations reveal the activation mechanism of mutations G12V and Q61L of Cdc42.

Cell division control protein 42 homolog (Cdc42), which contributes to multiple cellular processes including cell proliferation and migration, is a potential target for cancer therapy, especially in the intervention of tumor migration. Cdc42's mutants G12V and Q61L are discovered constitutively active, and the overexpression of them exhibits oncogenic activities. Here, using molecular dynamics (MD) simulations and dynamic analysis, we illustrated the activation mechanism of Cdc42 and Cdc42 .

Tetraethylthiuram disulphide alleviates pulmonary fibrosis through modulating transforming growth factor-β signalling.

Idiopathic pulmonary fibrosis (IPF) induces significant morbidity and mortality, for which there are limited therapeutic options available. Here, we found that tetraethylthiuram disulphide (disulfiram, DSF), a derivative of thiuram, used in the treatment of alcohol abuse, has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis via the attenuation of the fibroblast-to-myofibroblast transition, migration, and proliferation of fibroblasts. Furthermore, DSF inhibited the activation of primary pulmonary fibroblasts and fibroblast cell line under transforming growth factor-β 1 (TGF-β1) challenge.

Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening.

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer.

Polydopamine Nanoparticles for Deep Brain Ablation via Near-Infrared Irradiation.

Local resection or ablation remains an important approach to treat drug-resistant central neurological disease. Conventional surgical approaches are designed to resect the diseased tissues. The emergence of photothermal therapy (PTT) offers a minimally invasive alternative.

Benzothiophene-2-carboxamide derivatives as SENPs inhibitors with selectivity within SENPs family.

The SUMO (small ubiquitin-related modifier)-specific proteases (SENPs) are responsible for the cleavage of SUMO from its target proteins, thus play important roles in the dynamic SUMOylation and deSUMOylation processes. SENPs are related to a variety of human diseases including cancer and represent a new class of potential therapeutic targets with mechanism of action that is likely to be different from that of current clinically used drugs. However, potent inhibitors that are selective within the SENPs family members still remain a challenge due to their high homology.

Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic strategies. Lycorine (LYC), an alkaloid isolated from Amaryllidaceae family plants, exhibits effective anti-inflammatory, antiviral, and anti-tumor activities. In this study, we attempted to determine the effect of LYC on bleomycin (BLM)-induced IPF and NLRP3 inflammasome activation.

Mechanisms of transformation of nicotinamide mononucleotides to cerebral infarction hemorrhage based on MCAO model.

Objective: The study aims at discussing the effect of nicotinamide mononucleotides on protecting hemorrhagic transformation of cerebral infarction in the middle cerebral artery occlusion (MCAO) model.

Method: Male mice aged 4-5 weeks and weighing about 22-35 g in Shanghai Ninth People's Hospital are divided into three groups: sham group, collagenase intracerebral hemorrhage model (cICH + Vehicle) group and collagenase nicotinamide mononucleotide (cICH + NMN) group. Then, the intervention therapy research is carried out.

Discovery of small molecule agonists targeting neuropeptide Y4 receptor using homology modeling and virtual screening.

Neuropeptide Y4 receptor has the most significant effect on body weight and fat mass in its physiological functions, and the activation of Y4 receptor has explicit role on losing weight. The Y4 receptor has been successfully applied in the development of anti-obesity agent, thus representing a potential therapeutic target for obesity treatment. Here, we reported the first discovery of small molecule agonists targeting Y4 receptor: three Y4 receptor models with active and inactive conformations were built, each model was submitted following structure-based virtual screening, and finally six hits were identified as Y4 receptor agonists.

Inhibition of Cdc42-intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression, proliferation, migration, and tumor growth.

Cdc42 is a member of the Rho family of small GTPases that are at the crossroads of major oncogenic signaling pathways involved in both lung and prostate cancers. However, the therapeutic potential of Cdc42 regulation is still unclear due to the lack of pharmacological tools. Herein, we report that ZCL367 is a bona fide Cdc42 inhibitor that suppressed cancer development and ZCL278 can act as a partial Cdc42 agonist.

Dissociation mechanism of GDP from Cdc42 via DOCK9 revealed by molecular dynamics simulations.

Cell division control protein 42 homolog (Cdc42) influences a variety of cellular responses such as cell migration and polarity. Deregulation of Cdc42 has been associated with several human diseases and developmental disorders. Over-activation of Cdc42 through guanine nucleotide exchange factor (GEF) is a critical event for Cdc42 involved cancer metastasis.

Effectiveness of Screening Modalities in Colorectal Cancer: A Network Meta-Analysis.

The aim of the study was to evaluate on the effectiveness of screening modalities in the prevention of colorectal cancer (CRC) occurrence and deaths. General meta-analysis was performed to produce pooled estimates of the effect of CRC incidence and mortality using a search of PubMed, Web of Science, and the Cochrane Library for eligible studies from January 1992 to March 2016. A network meta-analysis was performed to synthetically compare the effectiveness of 5 frequently used screening modalities.

Efficacy and safety of long-term treatment with statins for coronary heart disease: A Bayesian network meta-analysis.

Background And Aims: Our study aims to evaluate the efficacy and safety of long-term treatment of statins for coronary heart disease (CHD).

Methods: Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE).

Identification of SENP1 inhibitors through in silico screening and rational drug design.

The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening.

Development and evaluation of a highly reliable assay for SUMO-specific protease inhibitors.

SUMOylation, as a post-translational modification of proteins, plays essential regulatory roles in a variety of pathological conditions. In the dynamic process of SUMOylation and deSUMOylation, SENPs (SUMO-specific proteases), in charge of deconjugation of SUMO (small ubiquitin-related modifier) from substrate proteins, have recently been found to be potential therapeutic targets for cancer treatment. A reliable and practical assay is much needed to accelerate the discovery of SENPs inhibitors.

Effects of Tongxinluo on myocardial fibrosis in diabetic rats.

Background: The aim of this study was to explore the effect of Tongxinluo on myocardial fibrosis in diabetic rats and its possible mechanism of action.

Methods: Diabetic rat models were established and then divided into three groups: control, diabetes, and Tongxinluo groups. Heart function and myocardial interstitial collagen volume fraction were investigated, and the protein and mRNA expression levels of transforming growth factor beta 1 (TGF-β1), Smad3, and Smad7 were measured.

In silico discovery of aminoacyl-tRNA synthetase inhibitors.

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNA. They play a pivotal role in protein synthesis and are essential for cell growth and survival. The aaRSs are one of the leading targets for development of antibiotic agents.