Type 2 diabetes (T2D) is a metabolic syndrome frequently associated with obesity and endoplasmic reticulum stress-mediated inflammation, which can trigger the unfolded protein response (UPR), impair insulin signaling, and promote apoptosis. To identify potential natural therapeutic candidates, this study investigated the mechanisms of action of 14 compounds from Uncaria tomentosa (UT), a medicinal plant from the Amazon rainforest, using in silico modeling. The study focused on the UPR, TRAF2/JNK pro-inflammatory signaling pathway, and insulin signaling pathways, which play key roles in T2D. Some of the UT compounds were docked against several human proteins involved in these pathways, and molecular dynamics simulations confirmed stable interactions between the target proteins (PERK, TRAF2, JNK, TNF-α, IRS-1, PI3K, AKT, GSK3β, and PPARγ) and four of the UT compounds, 5-Carboxystrictosidine, Cinchonain, Epicatechin and Mitraphylline. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties analyses were conducted to predict the four compounds, revealing suitable pharmacokinetic properties. These findings suggest that specific UT compounds may be used in experimental tests to whether investigate their therapeutic potential in managing T2D by modulating signaling pathways related to the conditions UPR, inflammation, and insulin resistance.
Bruna Freitas Marchi, Shraddha Parate, V. Jha et al.· International Journal of Mol...· 0 citations
PROteolysis TArgeting Chimeras (PROTACs) are bifunctional molecules designed to induce targeted protein degradation by forming a transient ternary complex between an E3 ubiquitin ligase and a protein of interest (POI), leading to the E3‐mediated ubiquitination of the POI and its subsequent proteasomal degradation. Although PROTACs have emerged as highly promising therapeutic tools, rational design remains challenging due to limited structural understanding of the resulting assemblies, the dynamic nature of the ternary interface, and the critical role of the linker. Herein, we present COMPASS (COmputational Modeling of PROTAC Assembly with Structure‐based Screening), a computational pipeline that allows the screening of linker libraries by assessing both ternary complex formation and ubiquitination potential. COMPASS functions as a high‐sensitivity negative filter, identifying linkers that cannot form productive complexes and enabling their elimination before synthesis. Benchmarking against 20 crystallographic structures yielded <6 Å Cα‐RMSD across all systems, outperforming existing methods. Retrospective validation across 8 distinct E3/POI systems (112 PROTACs) yielded 93% recall against degradation endpoints. Discriminative power is strongest when linker geometry is rate‐limiting, a regime complementary to the stability and cooperativity effects that static structural modeling cannot capture.
Sébastien Sueron, S. J. Mahdizadeh, Eric Chevet et al.· ChemMedChem· 0 citations
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