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Treatment of neovascular eye diseases like age-related macular degeneration require a compound that is not toxic to ocular cells, that can reduce inflammation and inhibit angiogenesis. Homoisoflavonoids, naturally occurring compounds isolated primarily from the Hyacinthaceae sub-family of plants, have shown promise as anti-inflammatories and inhibitors of angiogenesis. A series of sulphur analogues, (3-benzylidene thiochroman-4-ones), were synthesised via a three-step procedure. These compounds were evaluated for selectivity towards endothelial cells over non-endothelial cells and their ability to inhibit COX-II over COX-I.Their potential anti-angiogenic activity was assessed using the Matrigel tube formation assay. (3Z)-3-[(3-bromophenyl)methylidene]-6-methoxy-2,3-dihydro-4H-1-benzothiopyran-4-one (10) was most active with respect to anti-proliferation against human retinal endothelial cells (HREC cells) (GI₅₀ 3.07 μM). All demonstrated selectivity with all GI₅₀ values against retinal pigment epithelial cell line ARPE-19 >100 µM, with the exception of (3Z)-6-bromo-3-[(4-nitrophenyl)methylidene]-2,3-dihydro-4H-1-benzothiopyran-4-one (12), which was not toxic to either. (3Z)-3-[(3-bromophenyl)methylidene]-6-methoxy-2,3-dihydro-4H-1-benzothiopyran-4-one (10) showed significant reduction in angiogenesis properties in a Matrigel-based tube formation assay (38.79%, 5 µM, 56.41%, 10 µM). (3Z)-6-bromo-3-[(3-bromophenyl)methylidene]-2,3-dihydro-4H-1-benzothiopyran-4-one (7) was found to be the most active against COX-II with inhibition of 22.7 % (4.35 nM). The 3-benzylidene thiochroman-4-ones show promise as antiangiogenic agents, but limited selectivity to COX-II over COX-I.

Drug repurposing and repositioning are concepts that involve identifying alternative therapeutic uses for existing drug candidates or molecular series. During the COVID-19 pandemic, hundreds of antivirals were developed, many of which remain unexplored for other diseases. Concurrently, machine learning (ML) has become a valuable tool in early drug discovery for screening the most promising compounds for a target. In this work, an ExtraTrees ML model is developed to predict inhibitory activity against cruzain, the main cysteine protease of Trypanosoma cruzi, the causative agent of Chagas disease. The model is used to screen a proprietary library of peptidomimetic compounds originally designed to target SARS-CoV-2 M^pro and human cathepsin L. High-affinity cruzain inhibitors are identified, some containing P1 moieties not previously reported in cruzain inhibitors, expanding the known chemical space for this target. Selected hits are validated using isothermal titration calorimetry and some compounds display more favorable enthalpic and entropic contributions to binding than similar peptidomimetic nitrile-based inhibitors. Notably, this is achieved without highly lipophilic R-groups, preserving drug-like properties. This work also highlights how compound libraries derived from global health efforts can be effectively repurposed for neglected tropical diseases with ML models.

Factor VIIa (FVIIa) catalyzes the first step of the blood coagulation cascade. The expected wide therapeutic window between antithrombotic efficacy and bleeding risk makes FVIIa an attractive drug target. However, no FVIIa inhibitors have reached the market so far, mostly due to poor oral bioavailability. To date, in all ligand-bound X-ray crystal structures of FVIIa, the binding pocket of FVIIa is in an active, open form. Here, we present an X-ray crystal structure of the FVIIa–tissue factor complex with a bound oxazole-based inhibitor at 1.9 Å resolution, with an extensively remodeled active site and a collapsed S1 pocket. Using collectively 0.17 ms of atomistic molecular dynamics simulations, we observed conformational transitions between the collapsed and open forms of the S1 pockets of FVIIa and 12 other serine peptidases out of 16 studied, indicating an equilibrium of open and collapsed states of the S1 pocket in FVIIa and the majority of the serine proteases studied. Therefore, our results point to a general S1 pocket plasticity, which provides the basis for a completely new way of inhibiting FVIIa and other serine proteases.

The concept of a new Royal Australian Chemical Institute (RACI) Division covering Medicinal and Agricultural Chemistry came from the RACI Division of Physical Chemistry under whose auspices the First Australian Conference on Molecular Design and Structure-Activity Studies was held at the Victorian College of Pharmacy (VCP) in May 1981 as part of the Centenary Celebrations of the VCP. At the 7th National Convention of the RACI in Canberra in August 1982, the Medicinal and Agricultural Chemistry Group attracted some 100 participants, many of them new to the RACI. The success of these meetings was the basis of the formal proposal for the formation of the Division of Medicinal and Agricultural Chemistry which was unanimously approved by the RACI Council on May 24, 1983. The first stand-alone meeting of the new Division in October 1983 highlighted the case for a research-based drug industry in Australia. This editorial covers the period up until 1988, when the Division held the landmark Boden Conference on Biomolecular Design and Development and brought together many key people in the applications of medicinal chemistry in Australia.

The singlet oxygen quantum yield (SOQY) of photosensitizers (PSs) is a critical parameter in photodynamic therapy (PDT), directly linked to therapeutic efficacy by quantifying singlet oxygen generation. Traditional approaches to developing high-SOQY PSs are complex, involving elaborate molecular design and challenging SOQY measurements, which hinder rapid therapeutic advancement. This study constructs a comprehensive dataset to develop BiLSTM + attention (BA)-SOQY, a cutting-edge prediction model integrating bidirectional long short-term memory (BiLSTM) networks and attention mechanisms. BiLSTM captures long-term dependencies in sequential data, while the attention mechanism highlights critical input features, enabling efficient screening of potential PSs candidates. On the held-out test set, BA-SOQY achieves R² = 0.9140; validations on ESOL and FreeSolv datasets yield R² > 0.9, supporting robustness and generalization. Additionally, substructure masking interpretation strategy based on SMILES (SMIS-SMILES) is introduced. Combined with BA-SOQY, this forms the PSoSOQY platform, which not only provides accurate SOQY predictions but also reveals how substructures influence SOQY. These insights accelerate rational PSs design and high-throughput screening, driving progress in PDT research.

Developing novel drugs is a long and difficult process, particularly in oncology, where high attrition rates make clinical trials costly and time-consuming. In response, drug repurposing emerges as an efficient alternative: existing compounds can be used effectively in new therapeutic contexts. Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase involved in tumor progression, has emerged as a promising target for solid tumor treatment. To identify novel potential DDR1 inhibitors, we applied ESSENCE-Dock, an in-house consensus docking method designed to improve hit enrichment. Using this approach, we performed virtual screening of the DrugBank database, a comprehensive collection of Food and Drug Administration-approved and investigational drugs. To ensure novelty, we performed fingerprint dissimilarity analysis against known DDR1 inhibitors from BindingDB, prioritizing structurally distinct candidates. While several known DDR1 inhibitors ranked among the top-scoring compounds, we prioritized novel, structurally distinct candidates for testing. Biochemical IC₅₀ assays validated three previously unreported DDR1 inhibitors with nanomolar potency, while molecular dynamics simulations confirmed their stable binding within the DDR1 active site. Functional cell-based assays revealed inhibition of DDR1-mediated signaling and cancer cell migration. These findings demonstrate the effectiveness of our consensus-based virtual screening approach in drug repurposing and underscore its potential to streamline oncology drug development.

Posttranslational modifications of human enzymes play a crucial role in disease development. 4-hydroxynonenal (4-HNE), a lipid peroxidation product, can modify proteins and disrupt their function. Human cytochrome CYP4F11, involved in lipid metabolism and xenobiotic degradation, was previously shown to be inhibited by 4-HNE in a malaria model, where hemozoin-induced 4-HNE formation occurs in monocytes. However, structural changes to CYP4F11 upon 4-HNE modification had not been described. In this study, we investigated these changes using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and Raman spectroscopy. DSC thermograms revealed an increased energetic barrier to unfolding, suggesting structural reorganization. FTIR data, supported by computational analysis, showed a decrease in alpha-helix content (0.2–2.5%) and an increase in beta-structure (2.2–3.3%), along with altered disordered regions. Raman spectroscopy indicated significant changes in luminescence decay across emission wavelengths. These structural alterations induced by 4-HNE conjugation (protein lipoxidation) may significantly influence the enzymatic activity of CYP4F11, with potential implications for lipid metabolism and xenobiotic detoxification.

The synthesis of two bright epothilone-based fluorescent probes for microtubule imaging is described. Building on a tested strategy for the synthesis of epothilone-type structures, an analog of epothilone B with an extended C(6) substituent terminating in an alkyne group has been prepared. A Huisgen [3 + 2] cycloaddition of this analog with azide-functionalized derivatives of Alexa Fluor 488 and Janelia Fluor 646 gave bright fluorescent probes emitting in the green and far-red spectral range, respectively. Both probes bind to microtubules with high affinity and specifically label the microtubule network in A549 cells.

This cover shows the quinazolinone 4k approaching 26S proteasome, as discovered by limited proteolysis-based functional proteomics. Its interacting partners, the 20S β2 and β5 subunits, are depicted in white and light blue, respectively. The resulting inhibition of β5 chymotrypsin-like activity results in 4k cytotoxicity, represented by the green living cells turning into red, dying ones. More details can be found in the Research Article by Carmen Festa, Maria Chiara Monti, and co-workers (DOI: 10.1002/cmdc.202500728).

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose activation promotes phagocytosis and neuroprotection in Alzheimer's disease (AD) and related neurodegenerative disorders. While therapeutic efforts have largely focused on antibodies, small-molecule TREM2 modulators remain limited. Here, we applied a structure-based virtual screening workflow targeting a putative allosteric site on TREM2, guided by PyRod-derived pharmacophores from molecular dynamics simulations. Screening of the Enamine Collection (ESC) yielded 20 candidate compounds, three of which demonstrated binding in TRIC assays. The top hit, EN020, exhibited a K_D of 14.2 µM (MST) and 35.9 µM (SPR), and significantly enhanced microglial phagocytosis in BV2 cells, outperforming the known TREM2 agonist VG-3927. A preliminary structure–activity relationship (SAR) study, including synthetic and catalog-derived analogs, highlighted a narrow tolerance for scaffold modifications, with only T2V002 retaining partial TREM2 binding affinity. This work identifies EN020 as a novel small-molecule TREM2 modulator with functional activity, providing a framework for rational optimization toward potential AD therapeutics.