ACS Medicinal Chemistry Letters最新文献

COVID-19, caused by SARS-CoV-2, is a highly contagious disease with significant transmissibility and pathogenicity. The main protease of SARS-CoV-2 (M^pro or 3CL^pro) is crucial for viral replication, making it a key therapeutic target. Nirmatrelvir, a promising M^pro inhibitor, contains a trifluoroacetyl group in its P4 fragment, which presents opportunities for further optimization. This study aims to enhance the inhibitory activity of nirmatrelvir through structural modification of the P4 fragment. Using a computer-aided drug design (CADD) approach, 11 novel compounds were identified based on molecular docking scores, binding free energy, predicted ADMET properties, structural diversity, synthetic feasibility, and inhibitory activity. IC₅₀ measurements and molecular dynamics (MD) simulations demonstrated significant inhibitory potential for most compounds, with IC₅₀ values ranging from 0.0435–0.9989 μM. Notably, compounds 2–5a and 2–5f exhibited inhibitory activity against SARS-CoV-2 M^pro comparable to that of nirmatrelvir. These findings offer valuable insights for the development of anti-SARS-CoV-2 therapeutics.

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy with limited therapeutic options for many patients. Discoidin domain receptor 1 (DDR1), a transmembrane tyrosine kinase receptor, has been implicated in AML progression and represents a promising therapeutic target. In this study, we employed a hybrid virtual screening workflow that integrates deep learning-based binding affinity predictions with molecular docking techniques to identify potential DDR1 inhibitors. A multistage screening process involving PSICHIC, KarmaDock, Vina-GPU, and similarity-based scoring was conducted, leading to the selection of seven candidate compounds. The biological evaluation identified Compound 4 as a novel DDR1 inhibitor, demonstrating significant DDR1 inhibitory activity with an IC₅₀ of 46.16 nM and a 99.86% inhibition rate against Z-138 cells at 10 μM. Molecular dynamics simulations and binding free energy calculations further validated the stability and strong binding interactions of Compound 4 with DDR1. This study highlights the utility of combining deep learning models with traditional molecular docking techniques to accelerate the discovery of potent and selective DDR1 inhibitors. The identified compounds hold promise for further development as targeted therapies for AML.

A novel library of N-benzylphenoselenazine derivatives 8a–j were designed, synthesized, and evaluated as inhibitors of amyloid-beta (Aβ42) aggregation. In the thioflavin T-based fluorescence aggregation kinetics assay, compounds 8i and 8j exhibited excellent inhibition of Aβ42 aggregation (∼91% inhibition at 25 μM), and the activity was comparable to that of reference agents resveratrol (∼88%) and methylene blue (∼95% inhibition). Both compounds also demonstrated Aβ42 disaggregation properties (58% and 76% respectively at 25 μM) and antioxidant activity (80.5% and 59% respectively at 25 μM). In the cell culture studies, both 8i and 8j were able to reduce Aβ42-mediated cytotoxicity. Computational studies suggest that these compounds interact in a narrow channel formed by the N- and C-termini in the Aβ42 pentamer model to stabilize the assembly and prevent further aggregation. These results demonstrate the viability of the N-benzylphenoselenazines as promising candidates to target the amyloid cascade in Alzheimer’s disease.

Methionine adenosyltransferase 2a (MAT2a) has emerged as a promising therapeutic target due to its role in the synthetic lethality mechanism associated with MTAP-deficient tumors. In this study, we describe our efforts to identify a novel series of MAT2a inhibitors through a fragment-based joining strategy, leading to the development of a single molecule that occupies the allosteric site of the MAT2a dimer. Guided by the costructure of AZ-28 in complex with the MAT2a dimer, compound 9 was synthesized, demonstrating potent MAT2a inhibition (IC₅₀ = 20 nM) and significantly enhanced antiproliferative activity (IC₅₀ = 10 nM against HAP1MTAP^–/– cells). Moreover, compound 9 exhibited improved selectivity compared to both AZ-28 and AG-270.

The urgent need for unique small molecules to treat increasing resistance in gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus, has motivated several creative research endeavors over the past decade. Recent advances have been inspired by natural products such as pleuromutilin, discovered in high-throughput screens, or repurposed approved drugs like sorafenib. This microperspective spotlights bioactive compounds, ranging from natural products to small molecule scaffolds, that have been reported in recent literature, highlighting their mechanisms of action, structure–activity relationships, and future potential.

The invention in this patent relates to the use of phosphodiesterase-7 (PDE7) inhibitors with a spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1′-cyclohexan]-7-one scaffold for the treatment and prevention of diseases and syndromes associated with chronic fatigue, exhaustion, and exertional intolerance.

The invention in this patent relates to the use of phosphodiesterase-7 (PDE7) inhibitors with a spiro[[1,3]oxazolo[5,4-f]quinazoline-9,1'-cyclohexan]-7-one scaffold for the treatment and prevention of diseases and syndromes associated with chronic fatigue, exhaustion, and exertional intolerance.

Provided herein are novel compounds as 5-HT2A receptor modulators, pharmaceutical compositions, use of such compounds in treating psychiatric and neurological disorders and processes for preparing such compounds.

Recent advancements in cancer therapy focus on targeting critical mutations and regulatory pathways, particularly KRAS mutations and cyclin-dependent kinases (CDKs), which drive cancer progression. This Patent Highlight showcases the development of novel small-molecule inhibitors for KRAS and CDKs, highlighting their mechanisms of action, critical findings from preclinical studies, and the potential for improving therapeutic outcomes in cancers such as nonsmall cell lung cancer (NSCLC), colorectal, and pancreatic cancers.