Structure-Based Virtual Screening for Methyltransferase Inhibitors of SARS-CoV-2 nsp14 and nsp16.

The ongoing COVID-19 pandemic still threatens human health around the world. The methyltransferases (MTases) of SARS-CoV-2, specifically nsp14 and nsp16, play crucial roles in the methylation of the N7 and 2'-O positions of viral RNA, making them promising targets for the development of antiviral drugs. In this work, we performed structure-based virtual screening for nsp14 and nsp16 using the screening workflow (HTVS, SP, XP) of Schrödinger 2019 software, and we carried out biochemical assays and molecular dynamics simulation for the identification of potential MTase inhibitors.

Discovery of the small molecular inhibitors against sclerostin loop3 as potential anti-osteoporosis agents by structural based virtual screening and molecular design.

Sclerostin is a secreted glycoprotein that expresses predominantly in osteocytes and inhibits bone formation by antagonizing the Wnt/β-catenin signaling pathway, and the loop3 region of sclerostin has recently discovered as a novel therapeutic target for bone anabolic treatment without increasing cardiovascular risk. Herein, we used a structural based virtual screening to search for small molecular inhibitors selectively targeting sclerostin loop3. A novel natural product hit ZINC4228235 (THFA) was identified as the sclerostin loop3-selective inhibitor with a K value of 42.

Novel STAT3 oligonucleotide compounds suppress tumor growth and overcome the acquired resistance to sorafenib in hepatocellular carcinoma.

Signal transducer and activator of transcription 3 (STAT3) plays an important role in the occurrence and progression of tumors, leading to resistance and poor prognosis. Activation of STAT3 signaling is frequently detected in hepatocellular carcinoma (HCC), but potent and less toxic STAT3 inhibitors have not been discovered. Here, based on antisense technology, we designed a series of stabilized modified antisense oligonucleotides targeting STAT3 mRNA (STAT3 ASOs).

DiffDec: Structure-Aware Scaffold Decoration with an End-to-End Diffusion Model.

In molecular optimization, one popular way is R-group decoration on molecular scaffolds, and many efforts have been made to generate R-groups based on deep generative models. However, these methods mostly use information on known binding ligands, without fully utilizing target structure information. In this study, we proposed a new method, DiffDec, to involve 3D pocket constraints by a modified diffusion technique for optimizing molecules through molecular scaffold decoration.

GRELinker: A Graph-Based Generative Model for Molecular Linker Design with Reinforcement and Curriculum Learning.

Fragment-based drug discovery (FBDD) is widely used in drug design. One useful strategy in FBDD is designing linkers for linking fragments to optimize their molecular properties. In the current study, we present a novel generative fragment linking model, GRELinker, which utilizes a gated-graph neural network combined with reinforcement and curriculum learning to generate molecules with desirable attributes.

Deep learning-based design and screening of benzimidazole-pyrazine derivatives as adenosine A receptor antagonists.

The Adenosine A receptor (AAR) is considered a novel potential target for the immunotherapy of cancer, and AAR antagonists have an inhibitory effect on tumor growth, proliferation, and metastasis. In our previous studies, we identified a class of benzimidazole-pyrazine scaffolds whose derivatives exhibited the antagonistic effect but lacked subtype selectivity towards AAR. In this work, we developed a scaffold-based protocol that incorporates a deep generative model and multilayer virtual screening to design benzimidazole-pyrazine derivatives as potential selective AAR antagonists.

A novel PPARβ/FFA1 dual agonist Y8 promotes diabetic wound healing.

Background: Diabetes ulcer is one of the leading causes of disability and death in diabetics. Y8 [(2-(2-fluoro-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy) phenoxy)acetic acid)], a dual agonist of peroxisome proliferation activated receptorβ (PPARβ) and free fatty acid receptor 1 (FFA1/FFAR1/GPR40), a new compound molecule with the potential for diabetes ulcer treatment.

Objective: To research the effect of the dual target agonist Y8 and its mechanism of action in the treatment of diabetic ulcers.

Discovery and Design of Novel Cyclic Peptides as Specific Inhibitors Targeting CCN2 and Disrupting CCN2/EGFR Interaction for Kidney Fibrosis Treatment.

Kidney fibrosis is a serious consequence of chronic kidney disease (CKD), and currently, there is no effective pharmacological treatment available. Cellular communication network-2 (CCN2/CTGF) is an extracellular matrix (ECM) protein that regulates the fibrotic process by activating the epidermal growth factor receptor (EGFR) signaling pathway. We herein present the discovery and structure-activity relationship study of novel peptides targeting CCN2 to develop potent and stable specific inhibitors of the CCN2/EGFR interaction.

3D Conformational Generative Models for Biological Structures Using Graph Information-Embedded Relative Coordinates.

Developing molecular generative models for directly generating 3D conformation has recently become a hot research area. Here, an autoencoder based generative model was proposed for molecular conformation generation. A unique feature of our method is that the graph information embedded relative coordinate (GIE-RC), satisfying translation and rotation invariance, was proposed as a novel way for encoding molecular three-dimensional structure.

DRlinker: Deep Reinforcement Learning for Optimization in Fragment Linking Design.

Fragment-based drug discovery is a widely used strategy for drug design in both academic and pharmaceutical industries. Although fragments can be linked to generate candidate compounds by the latest deep generative models, generating linkers with specified attributes remains underdeveloped. In this study, we presented a novel framework, DRlinker, to control fragment linking toward compounds with given attributes through reinforcement learning.

Synthesis of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid molecules and biological evaluation against colon cancer cells as selective Akt kinase inhibitors.

A series of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid compounds were synthetized through a one-pot gold-catalyzed oxidative cyclization and Aldol-type addition cascade reaction of homopropargylic alcohols with 9,10-phenanthrenequinone. The cytotoxicity of newly synthesized compounds was evaluated in CCK8 assay against different human cancer cells, showing significantly antiproliferative activity against tested tumor cell lines with a lowest IC value of 0.92 μM over HCT-116.

Surface urban heat island and its relationship with land cover change in five urban agglomerations in China based on GEE.

The development of urbanization has changed the original land cover and exacerbated the urban heat island effect, seriously affecting the sustainable development of the ecological environment. Research on urban heat island characteristics and land cover changes in five major urban agglomerations in China to provide a reference for preventing thermal environmental risks and urban agglomeration construction planning. This paper estimates the surface urban heat island intensity (SUHII) of the five major urban agglomerations in China from 2003 to 2019 based on Google Earth Engine (GEE) through the urban-rural dichotomy, analyzes their trends through the Sen + M-K trend analysis method, and combines the detrending rate matrix to analyze the impact of land cover type shift on urban heat island change.

Discovery of Novel Benzo[4,5]imidazo[1,2-]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A Adenosine Receptor Antagonists.

The blockade of A adenosine receptor (AAR) activates immunostimulatory response through regulating signaling in tumor microenvironment. Thus, AAR has been proposed as a promising target for cancer immunotherapy. In this work, we designed a new series of benzo[4,5]imidazo[1,2-]pyrazin-1-amine derivatives bearing an amide substitution at 3-position to obtain potent antitumor antagonist .

Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer.

Advanced gastric cancer (GCa) remains highly lethal due to the lack of effective therapies. Identifying promising therapeutic targets and developing effective treatment against GCa are urgently needed. Through mRNA and protein analysis of GCa clinical tumor samples, we found that autophagy-related gene 4B (ATG4B) was overexpressed in GCa tumors and that its high expression was associated with patients' poor prognosis.

Ilicicolin A Exerts Antitumor Effect in Castration-Resistant Prostate Cancer Via Suppressing EZH2 Signaling Pathway.

The Polycomb protein enhancer of zeste homolog 2 (EZH2) has critical roles in prostate cancer (PCa) progression and drug-resistance, which remains an obstacle for PCa treatment. Enzalutamide (ENZ) is a second-generation androgen receptor antagonist employed for treatment of metastatic castration-resistant prostate cancer A considerable proportion of tumors eventually develop resistance during treatment. Thus, agents that can overcome resistance to PCa are needed urgently.

Prediction of Spatiotemporal Invasive Risk of the Red Import Fire Ant, (Hymenoptera: Formicidae), in China.

The red imported fire ant, (Hymenoptera: Formicidae) is an invasive pest, and it has spread rapidly all over the world. Predicting the suitable area of growth in China will provide a reference that will allow for its invasion to be curbed. In this study, based on the 354 geographical distribution records of , combined with 24 environmental factors, the suitable areas of growth in China under current (2000s) and future (2030s and 2050s) climate scenarios (SSPs1-2.

Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer.

Human dihydroorotate dehydrogenase (DHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent DHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus , and several of them showed pronounced inhibitions against DHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468.

The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants.

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer.

Microsecond timescale MD simulations at the transition state of HMGR predict remote allosteric residues.

Understanding the mechanisms of enzymatic catalysis requires a detailed understanding of the complex interplay of structure and dynamics of large systems that is a challenge for both experimental and computational approaches. More importantly, the computational demands of QM/MM simulations mean that the dynamics of the reaction can only be considered on a timescale of nanoseconds even though the conformational changes needed to reach the catalytically active state happen on a much slower timescale. Here we demonstrate an alternative approach that uses transition state force fields (TSFFs) derived by the quantum-guided molecular mechanics (Q2MM) method that provides a consistent treatment of the entire system at the classical molecular mechanics level and allows simulations at the microsecond timescale.

Targeting castration-resistant prostate cancer with a novel ROR antagonist elaiophylin.

Prostate cancer (PCa) patients who progress to metastatic castration-resistant PCa (mCRPC) mostly have poor outcomes due to the lack of effective therapies. Our recent study established the orphan nuclear receptor ROR as a novel therapeutic target for CRPC. Here, we reveal that elaiophylin (Elai), an antibiotic from , is a novel ROR antagonist and showed potent antitumor activity against CRPC and .

Design, synthesis and biological evaluation of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine: Towards adenosine A receptor (A AR) antagonist.

Antagonists of adenosine receptor are under exploration as potential drug candidates for treatment of neurological disorders, depression, certain cancers and potentially used as a cancer immunotherapy. Herein, we describe design and synthesis of novel scaffold benzo[4,5]imidazo [1,2-a]pyrazin-1-amine (6) derivatives. All the compounds were evaluated for A AR antagonist activity and displayed encouraging results (IC 9-300 nM) of A AR antagonist binding affinity in biochemical assay.

Blue Light-Promoted Formal [4+1]-Annulation of Diazoacetates with -Aminoacetophenones: Synthesis of Polysubstituted Indolines and Computational Study.

A blue light-promoted formal [4+1]-annulation of diazoacetates with -aminoacetophenones has been reported, which provides an environmentally friendly method for the synthesis of polysubstituted indoline derivatives in moderate to good yields with excellent diastereoselectivities. Detailed mechanistic studies through density functional theory calculations reveal that the ()-enol species is the key intermediate in this transformation, and the excellent diastereoselectivity is enabled -bonding in the intramolecular Aldol-type addition.

Strain-Induced Nucleophilic Ring Opening of Donor-Acceptor Cyclopropenes for Synthesis of Monosubstituted Succinic Acid Derivatives.

1,2,3-Trisubstituted donor-acceptor cyclopropenes (DACPs) generated in situ from enoldiazo compounds react with nucleophiles to form α-substituted succinic acid derivatives in high yields. Initial dirhodium(II) carboxylate catalysis rapidly converts enoldiazo-acetates or -acetamides to DACPs that undergo catalyst-free Favorskii ring opening with amines, and also with anilines, alcohols, and thiols, when facilitated by catalytic amounts of 4-dimethylaminopyridine (DMAP). This methodology provides easy access to mixed esters and amides of monosubstituted succinic acids, including derivatives of naturally occurring compounds.

The hydrolytic water molecule of Class A β-lactamase relies on the acyl-enzyme intermediate ES* for proper coordination and catalysis.

Serine-based β-lactamases of Class A, C and D all rely on a key water molecule to hydrolyze and inactivate β-lactam antibiotics. This process involves two conserved catalytic steps. In the first acylation step, the β-lactam antibiotic forms an acyl-enzyme intermediate (ES*) with the catalytic serine residue.