Interest in electron diffraction (ED) for structural characterization of both proteins and small molecules has grown significantly over the last decade. While ab initio phasing methods remain the gold standard for ED data from small-molecule samples, radiation beam damage during data collection and poor crystallinity of the nanocrystalline sample can make this method unfeasible - particularly for challenging molecules that exhibit conformational flexibility. Molecular replacement (MR) is the most commonly used phasing method for protein ED data and can circumnavigate issues related to diminished data quality. However, its application to small molecules has been limited due to the lack of methods for generating optimal trial conformations. Herein, a high-throughput automated molecular replacement workflow has been developed to solve a novel ED structure of corilagin, a macrocyclic gallotannin with pharmaceutical relevance, which could not be solved with ab initio phasing. The method was validated against three similar macrocycles with known structures (paritaprevir-α, paritaprevir-β and grazoprevir) at varying data resolution limits (1.0, 1.2, 1.4, 1.5, 1.6, 1.8 and 2.0 Å). At all these resolutions for all three structures, the developed workflow was successful and produced solutions with R factors and RMSD values within acceptable limits of the ab initio solved structure.

A potent novel small molecule GLP-1R agonist identified by rational design and CADD.

Thermal sonogenetics for adoptive cell transfer therapy.

Mutations in the KCNJ5 (potassium inwardly rectifying channel subfamily J member 5) gene, encoding an inwardly rectifying potassium channel, can drive aldosterone overproduction in a subset of aldosterone-producing adenomas and in familial hyperaldosteronism type III. Our objective was to identify small molecule compounds that specifically antagonize mutant KCNJ5 channels. Virtual screening of over 6 million small molecules identified compounds that putatively bind to KCNJ5 channels. The effect of 108 of these candidates was evaluated in vitro in human adrenocortical cells (HAC15) with inducible expression of wild-type or mutated forms of KCNJ5. Assessment encompassed cell viability, flow cytometry, gene expression, and adrenal steroid quantification via liquid chromatography-tandem mass spectrometry. Compounds antagonizing mutated KCNJ5 function were identified by evaluating their ability to rescue adrenal cell death induced by overexpression of mutant KCNJ5. A spiroquinoline compound, referred to as compound 81 (C81), effectively rescued cell death induced by KCNJ5 L168R in both monolayer and spheroid HAC15 cell cultures. C81 treatment caused a 69% to 85% reduction in CYP11B2 (aldosterone synthase) mRNA levels induced by KCNJ5 L168R, G151R, or T158A expression, compared with untreated cells. C81 also reduced aldosterone secretion by 65% in cells expressing KCNJ5 L168R and decreased 18-oxocortisol and 18-hydroxycortisol production by 78% and 90%, respectively. However, C81 had no significant effect on steroid secretion in cells overexpressing wild-type KCNJ5. C81 shows potential as a small molecule antagonist to specifically target pathological aldosterone secretion in familial hyperaldosteronism type III or KCNJ5-mutated aldosterone-producing adenomas. These findings suggest new avenues for genotype-based primary aldosteronism diagnostics and targeted treatments, contributing to personalized patient care.

Identification and validation of small molecules with mucin-selective regiospecific binding in the gastrointestinal tract.

Caveolin-1 regulates cellular cholesterol homeostasis and its potential as an atherosclerosis therapy target.

Radicals formed during operation of polymer electrolyte fuel cells, particularly during accelerated stress tests (AST), chemically degrade hydrocarbon proton exchange membranes (HC PEMs). In HC PEMs, the path from initial chemical attack over the evolution of membrane damage to failure is not yet well understood. This is evident when assessing different classes of HC PEMs in OCV hold ASTs: while chemical degradation occurs in all systems, expression of the evolution of membrane damage can differ vastly. This work combines an extensive OCV hold study with a complimentary gamma-radiolysis investigation on model small molecules for the first time. Our experiments reveal that the in-situ AST lifetime trends of HC PEMs correlate with the susceptibility of phenyl sulfonates – featuring to some extent comparable electronic configurations – to undergo degradative chain-reactions when exposed to the highly oxidizing radicals generated during the radiolysis of aqueous solutions. Our conclusions aim to incite the discussion on underlying radical stability of different HC PEMs, and we propose that electron-rich, poly(phenylene) type materials more likely undergo chemical degradation pathways that delay OCV failure, i.e. “suppress” membrane damage, when compared to electron-poor poly(phenylene sulfone) and poly(ether ether ketone) type materials. • First comparative OCV hold assessment of HC PEMs focusing on evolution of inevitable membrane damage. • For hydrocarbon constituents, Ce(III) acts as a repair agent and not as radical scavenger. • Radical-induced degradation is suppressed for compounds with low ionization potential. • PEM chemistry may limit high frequency resistance measurements as metric for membrane's state-of-health. • Complexity of cell environment constrains translation of findings from small molecules to membrane degradation.

Inwardly rectifying potassium (KIR) channels are essential regulators of membrane potential in excitable and non-excitable tissues. Although KIR channels exhibit a biophysical preference for potassium influx due to voltage-dependent block of outward current by polyamines and Mg2+, under physiological conditions, they predominantly mediate K+ efflux. This outward current not only is essential for stabilizing the resting membrane potential, limiting cellular excitability and coordinating rhythmic activity in excitable tissues such as the heart and muscle, but also functions in endocrine and exocrine organs and neural tissues. A growing list of pathogenic KIR mutations that reduce or abolish channel activity has been linked to channelopathies, including Andersen syndrome and EAST/SeSAME syndrome, among others. These loss-of-function phenotypes underscore the therapeutic need for selective KIR channel activators. However, pharmacological tools remain limited and subtype-selective activation is rare. Small molecules such as ML297 selectively activate Kir3.1/3.2-containing channels, whereas GiGA1 and VU0529331 target Kir3.2-containing subunits. Several clinically used drugs (e.g. propafenone) modulate Kir2.1 and novel compounds such as GPV0057 show improved selectivity. However, no KIR channel activators have advanced to clinical trials and key subtypes such as Kir1.1 and Kir7.1 lack known openers. This review evaluates the current knowledge of KIR-targeted agonists, with a focus on their potential to address PIP2-dependent loss-of-function mutations in KIR channels. We emphasize the urgent need for subtype-specific KIR openers, the development of PIP2-independent mechanisms of action and comprehensive preclinical characterization to overcome translational barriers. Addressing these challenges may provide new therapeutic opportunities for rare channelopathies associated with KIR channel dysfunction.

Clear cell renal cell carcinoma (ccRCC) is highly aggressive and exhibits significant heterogeneity, making early diagnosis challenging. Carbonic anhydrase IX (CAIX) is highly expressed in the majority of ccRCC cases while exhibiting minimal expression in normal tissues, rendering it an ideal target for molecular imaging and targeted therapy. In recent years, various CAIX-targeted radiopharmaceuticals based on antibodies, small molecules and Affibodies have rapidly advanced in PET/SPECT imaging and targeted radionuclide therapy. Preclinical studies have demonstrated that probes labeled with 89Zr, 124I, 68Ga, 18F, 99mTc, 111In and 64Cu exhibit an excellent imaging performance and tumor specificity. Radiolabeled immunotherapies using 177Lu and 225Ac have effectively inhibited tumor growth in animal models, and early clinical studies suggest controllable safety in patients with metastatic ccRCC, although bone marrow suppression and potential nephrotoxicity remain concerns. Overall, CAIX-targeted radiopharmaceuticals provide important avenues for early diagnosis, intraoperative localization, recurrence monitoring and personalized treatment of ccRCC. Future efforts should focus on clinical trials and dosimetry optimization to facilitate clinical translation of these agents.

The implementation of small molecule agonists and antagonists to elucidate gonadotropin receptor structure, function and physiology.

FNDR-11124, a broad-spectrum small molecule inhibitor of viral RNA polymerase, restricts replication of SARS-CoV-2 and Influenza virus in vitro and in vivo.

β-catenin: A crucial transcriptional activator of KSHV latency genes and small molecule target in primary effusion lymphoma.

MomordinIc suppresses breast cancer growth by targeting ACTL8‑dependent glutamine metabolism and PI3K/AKT/mTOR-MYC.

Targeting mitochondrial complexes for cancer therapy.

Design of new thiophene-based hole transport materials for high-efficiency perovskite solar cells: A DFT study and Monte Carlo simulations.

Phenylboronic acid modification and small-molecule assembly to enhance the safety of resiquimod and its synergistic anti-tumor efficacy with paclitaxel.

Molecular interactions between ticks (Ixodidae) and cattle: Salivary proteins, host immune modulation, and pathogen transmission.

Direct-acting antivirals and beyond: emerging approaches to targeting viral RNA and ribonucleoprotein complexes.

UV filter - cyclodextrin complexes are investigated in silico in an aqueous environment using all-atom molecular dynamics simulations in the isothermal-isobaric statistical ensemble. The UV filters considered herein are octocrylene and avobenzone, which are used in commercial sunscreen products and together provide broad-spectrum skin protection (covering UV-A to UV-B radiation). The selected host molecules are β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). In general, cyclodextrins have been assessed for protecting UV filters against photodegradation and oxidation, as well as for their ability to restrict UV filter permeation into deep skin layers. In all simulations, the starting point involves the UV filters and cyclodextrin molecules in the unbound state to determine whether noncovalent complexation is a spontaneous process. The main goal of this study is to examine in detail the complexes from a nanoscopic point of view, as well as the complexation process itself, paying particular attention to the thermodynamic description and the stability of the formed supramolecular complexes. In the framework of our analysis, several properties are calculated and, when possible, comparisons are made with published experimental data. Concerning thermodynamics, the binding free energy is estimated by applying a modified version of the Linear Interaction Energy (LIE) method. This method has been successfully applied in a number of studies involving complexes formed between cyclodextrins and small organic molecules. In the case of avobenzone, which contains a β-diketone group, both keto and enol forms are considered due to their tautomeric equilibrium and their distinct roles in photoprotection and photodegradation mechanisms.

Monaprenylindole A, a prenylated indole derivative from marine-derived Streptomyces sp., accelerates wound healing through the enhancement of keratinocyte motility via the modulation of cytoskeletal remodeling and growth factor pathways.