Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear.

Discovery of highly potent phosphodiesterase-1 inhibitors by a combined-structure free energy perturbation approach.

Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discovery by identifying highly potent ligands. By simulating the change from one compound structure to another, the relative binding free energy (RBFE) change can be calculated based on the theoretically rigorous free energy perturbation (FEP) method. However, existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states, which can lead to increased computational costs to obtain the converged results.

A Bait-and-Hook Hydrogel for Net Tumor Cells to Enhance Chemotherapy and Mitigate Metastatic Dissemination.

: Lung cancer is an aggressive disease with rapid progression and a high rate of metastasis, leading to a significantly poor prognosis for many patients. While chemotherapy continues to serve as a cornerstone treatment for a large proportion of lung cancer patients, expanding preclinical and clinical evidence indicates that chemotherapy may promote tumor metastasis and cause side effects. : We develop an injectable bait-and-hook hydrogel (BH-gel) for targeted tumor cell eradication, which embedded doxorubicin liposomes as cytotoxic agents and CXCL12 as a chemoattractant to capture and kill tumor cells.

RED-E-Function-Based Equilibrium Parameter Finder: Finding the Best Restraint Parameters in Absolute Binding Free Energy Calculations.

Free energy perturbation (FEP)-based absolute binding free energy (ABFE) calculations have emerged as a powerful tool for the accurate prediction of ligand-protein binding affinities in drug discovery. The restraint addition is crucial in FEP-ABFE calculations; however, due to the non-orthogonal couplings between the restrained degrees of freedom, it typically requires numerous λ windows to ensure the phase-space overlap during restraint addition. This study introduces the RED-E-function-based equilibrium parameter finder (REPF), a novel method that relies on harmonic restraints to optimize the equilibrium values in restraints, enhancing phase-space overlap and improving the convergence of the restraint addition.

Cross-Generational Exposure to Low-Density Polyethylene Microplastics Induced Hyperactive Responses in Offsprings.

The extensive application of plastic products in daily human life has led to the accumulation of microplastics (MPs) in agricultural soil. However, little is known about the cross-generational toxicity of MPs on terrestrial invertebrates. In this study, two-generational was exposed to low-density polyethylene (LDPE, 0-5%, w/w) for 98 days to reveal the cross-generational toxicity and the underlying mechanisms.

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood.

Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC of 4.

Convergence-Adaptive Roundtrip Method Enables Rapid and Accurate FEP Calculations.

The free energy perturbation (FEP) method is a powerful technique for accurate binding free energy calculations, which is crucial for identifying potent ligands with a high affinity in drug discovery. However, the widespread application of FEP is limited by the high computational cost required to achieve equilibrium sampling and the challenges in obtaining converged predictions. In this study, we present the convergence-adaptive roundtrip (CAR) method, which is an enhanced adaptive sampling approach, to address the key challenges in FEP calculations, including the precision-efficiency tradeoff, sampling efficiency, and convergence assessment.

Discovery of Oxidized -Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new -terphenyl derivatives, talaroterphenyls A-D (-), together with three biosynthetically related known ones (-), were obtained from the mangrove sediment-derived sp. SCSIO 41412. Compounds - are rare -terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources.

Ergone Derivatives from the Deep-Sea-Derived Fungus YPGA10 and 25,28-Dihydroxyergone-Induced Apoptosis in Human Colon Cancer SW620 Cells.

Ten new ergone derivatives (-) and five known analogues (-) were isolated from the deep-sea-derived fungus YPGA10. The structures including the absolute configurations were established by detailed analysis of the NMR spectroscopic data, HRESIMS, ECD calculation, and coupling constant calculation. All the structures are characterized by a highly conjugated 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one nucleus.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed.

Regulation of Burkholderia cenocepacia virulence by the fatty acyl-CoA ligase DsfR as a response regulator of quorum sensing signal.

Quorum sensing (QS) is a cell-to-cell communication mechanism mediated by small diffusible signaling molecules. Previous studies showed that RpfR controls Burkholderia cenocepacia virulence as a cis-2-dodecenoic acid (BDSF) QS signal receptor. Here, we report that the fatty acyl-CoA ligase DsfR (BCAM2136), which efficiently catalyzes in vitro synthesis of lauryl-CoA and oleoyl-CoA from lauric acid and oleic acid, respectively, acts as a global transcriptional regulator to control B.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet.

The application of drug behavior management methods in the treatment of dental fear and oral diseases in children: A review.

Oral behavior management methods include basic behavior management methods and drug behavior management methods. In many cases, dental treatment that cannot be done simply through basic behavior management is not possible. The uncooperative behavior of children with dental fear in oral treatment has increased the demand for medication based behavior management methods.

PDE12 disrupts mitochondrial oxidative phosphorylation and mediates mitochondrial dysfunction to induce oral mucosal epithelial barrier damage in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic oral mucosal disease. The pathological changes of OSF include epithelial damage and subepithelial matrix fibrosis. This study aimed to reveal the epithelial injury mechanism of OSF.

Accelerating and Automating the Free Energy Perturbation Absolute Binding Free Energy Calculation with the RED-E Function.

The accurate prediction of the binding affinities between small molecules and biological macromolecules plays a fundamental role in structure-based drug design, which is still challenging. The free energy perturbation-based absolute binding free energy (FEP-ABFE) approach has shown potential in its reliability. To correctly calculate the energy related to the ligand being restrained by the receptor, additional restraints between the ligand and the receptor are needed.

Regulation of the physiology and virulence of Ralstonia solanacearum by the second messenger 2',3'-cyclic guanosine monophosphate.

Previous studies have demonstrated that bis-(3',5')-cyclic diguanosine monophosphate (bis-3',5'-c-di-GMP) is a ubiquitous second messenger employed by bacteria. Here, we report that 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) controls the important biological functions, quorum sensing (QS) signaling systems and virulence in Ralstonia solanacearum through the transcriptional regulator RSp0980. This signal specifically binds to RSp0980 with high affinity and thus abolishes the interaction between RSp0980 and the promoters of target genes.

3D-SMGE: a pipeline for scaffold-based molecular generation and evaluation.

In the process of drug discovery, one of the key problems is how to improve the biological activity and ADMET properties starting from a specific structure, which is also called structural optimization. Based on a starting scaffold, the use of deep generative model to generate molecules with desired drug-like properties will provide a powerful tool to accelerate the structural optimization process. However, the existing generative models remain challenging in extracting molecular features efficiently in 3D space to generate drug-like 3D molecules.

Inhibition of AKR1Cs by liquiritigenin and the structural basis.

In vivo and in vitro studies have confirmed that liquiritigenin (LQ), the primary active component of licorice, acts as an antitumor agent. However, how LQ diminishes or inhibits tumor growth is not fully understood. Here, we report the enzymatic inhibition of LQ and six other flavanone analogues towards AKR1Cs (AKR1C1, AKR1C2 and AKR1C3), which are involved in prostate cancer, breast cancer, and resistance of anticancer drugs.

Identification of Novel Quinolin-2(1)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1)-ones were designed rationally, leading to compound with an IC of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties.

Super toughened blends of poly(lactic acid) and poly(butylene adipate-co-terephthalate) injection-molded foams via enhancing interfacial compatibility and cellular structure.

Biodegradable poly(lactic acid) (PLA) foams have drawn increasing attention due to environmental challenges and petroleum crisis. However, it still remains a challenge to prepare PLA foams with fine cellular structures and high impact property, which significantly hinders its widespread application. Herein, phase interface-enhanced PLA/ poly(butylene adipate-co-terephthalate) (PBAT) blend foam, modified by a reactive compatibilizer through a simple reactive extrusion, was produced via a core-back foam injection molding technique.

Anti-Inflammatory Salidroside Delivery from Chitin Hydrogels for NIR-II Image-Guided Therapy of Atopic Dermatitis.

Atopic dermatitis (AD) is the most common heterogeneous skin disease. Currently, effective primary prevention approaches that hamper the occurrence of mild to moderate AD have not been reported. In this work, the quaternized β-chitin dextran (QCOD) hydrogel was adopted as a topical carrier system for topical and transdermal delivery of salidroside for the first time.

Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-B transcription regulation and activating cAMP/CREB axis.

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated and by a potent and selective PDE1 inhibitor .

Structure Revisions of Phenolic Bisabolane Sesquiterpenes and a Ferroptosis Inhibitor from the Marine-Derived Fungus YPH93.

Seven new phenolic bisabolane sesquiterpenoids (-), along with 10 biogenetically related analogues (-), were obtained from the deep-sea-derived fungus YPH93. The structures were elucidated based on extensive analyses of the spectroscopic data. Compounds - are the first examples of phenolic bisabolanes that contain two hydroxy groups attached to the pyran ring.

Free energy perturbation-based large-scale virtual screening for effective drug discovery against COVID-19.

As a theoretically rigorous and accurate method, FEP-ABFE (Free Energy Perturbation-Absolute Binding Free Energy) calculations showed great potential in drug discovery, but its practical application was difficult due to high computational cost. To rapidly discover antiviral drugs targeting SARS-CoV-2 M and TMPRSS2, we performed FEP-ABFE-based virtual screening for ∼12,000 protein-ligand binding systems on a new generation of Tianhe supercomputer. A task management tool was specifically developed for automating the whole process involving more than 500,000 MD tasks.