ACS Medicinal Chemistry Letters最新文献

Cancer continues to pose a major global health challenge due to its metabolic complexity. Pyruvate Kinase M2 (PKM2), a key glycolytic enzyme, is central to tumor progression and metastasis. To facilitate targeted drug discovery, we introduce PKM2Pred (https://pkm2pred.vercel.app/), a machine learning based freely accessible web server that classifies compounds as activators, inhibitors, or decoys and predicts their AC₅₀ range. Built on a Random Forest classifier, the model achieved 94% accuracy and a Matthews Correlation Coefficient of 90.02%. A bootstrapped regression model estimated bioactivity ranges with confidence intervals, offering flexibility between prediction and range. The top three key molecular descriptors, such as WTPT-5, SRW9, and nHeteroRing, emerged as the most important statistical descriptors based on their percentage importance of 12.5, 8.2, and 5.8, respectively. Thus, PKM2Pred offers rapid, reliable, and cost-effective computational insight for anticancer drug discovery.

Zervimesine is a small molecule, able to cross the blood–brain barrier, readily available by straightforward organic chemistry processes, showing few “off-target” effects, but displays a potent and selective S2R modulator profile. Evidence suggests Zervimesine can protect synapses and neurons by preventing the toxic effects of soluble Aβ oligomers.

Ligand efficiency (LE), defined as the negative binding free energy per heavy atom, is a widely used metric in medicinal chemistry. Yet its mathematical construction embeds a strong size bias that distorts cross-size comparisons, and size-independent variants inherit sensitivity to the arbitrary choice of standard state. This study reviews normalization pitfalls, addresses uncertainty propagation, and introduces a state-invariant, size-normalized metric for efficiency-guided optimization from fragments to leads.

Recent inventions have unveiled two complementary therapeutic strategies: cyclic peptides that trigger the lysosomal degradation of the epidermal growth factor receptor (EGFR), and soluble peptide–MHC constructs that suppress autoreactive T-cell receptors in multiple sclerosis. Together, these innovations highlight emerging frameworks for precision control of receptor signaling and adaptive immunity using structurally defined peptide modulators.

Herein we report the first synthesis of the proposed structure of a benzodiazocine natural product, peganutonin A. Considering the druggable nature of benzodiazocine and its limited exploration in the field of medicinal chemistry, we generalized the approach and created a library of compounds useful for various biological activities. Key steps in present approach include tryptamine cyclization facilitated by tert-butyl hypochlorite and cleavage of the fused indole ring using ozonolysis. Preliminary screening of the synthesized compounds resulted in potent antiviral compounds against the SARS-CoV-2 virus.

Recent patents unveil a new wave of psychedelic analogs optimized for 5-HT₂A receptor modulation, reduced adverse effects, and tunable duration of action. By refining DMT and psilocin scaffolds through prodrug design, fluorination, and structure–activity exploration, these innovations promise safer, shorter-acting psychedelic medicines that align with clinical workflow and improve therapeutic predictability for psychiatric disorders.

New-generation KRAS G12C inhibitors demonstrate enhanced activity in both peripheral and central nervous system malignancies. Frontier Medicines’ pyridopyrimidines and Novartis’s spiro-indazole inhibitor (opnurasib) overcome resistance mechanisms by targeting both GDP- and GTP-bound KRAS states. Their blood–brain barrier permeability and synergy with immune checkpoint inhibitors represent a transformative advance for KRAS-driven cancers, especially metastatic nonsmall cell lung cancer (NSCLC).

Recent innovations in targeted protein degradation (TPD) extend beyond small-molecule PROTACs to encompass engineered peptides and recyclable ligand systems. Two complementary strategies─EGFR-directed peptide complexes and PKC-targeting bifunctional degraders─highlight a mechanistic expansion of TPD into kinase-driven pathologies, offering new avenues for addressing cancer resistance, immune dysregulation, and receptor signaling with enhanced precision and modularity.

Provided herein are novel compounds as PI3Kα inhibitors, pharmaceutical compositions, use of such compounds in treating cancer, and processes for preparing such compounds.

Provided herein are novel compounds as ACC inhibitors, pharmaceutical compositions, use of such compounds in treating acne, and processes for preparing such compounds.