Small Angle X-ray Scattering,Molecular Modeling,and Chemometric Studies from a Thrombin-Like (Lmr-47) Enzyme of Lachesis m. rhombeata Venom

Introduction: Snakebite envenomation is considered a neglected tropical disease, and SVTLEs critical elements are involved in serious coagulopathies that occur on envenoming. Although some enzymes of this group have been structurally investigated, it is essential to characterize other proteins to better understand their unique properties such as the Lachesis muta rhombeata 47 kDa (Lmr-47) venom serine protease. Methods: The structure of Lmr-47 was studied in solution, using SAXS, DLS, CD, and in silico by homology modeling. Molecular docking experiments simulated 21 competitive inhibitors. Results: At pH 8.0, Lmr-47 has an Rg of 34.5 ± 0.6 Å, Dmax of 130 Å, and SR of 50 Å, according to DLS data. Kratky plot analysis indicates a rigid shape at pH 8.0. Conversely, the pH variation does not change the center of mass’s intrinsic fluorescence, possibly indicating the absence of fluorescent amino acids in the regions affected by pH variation. CD experiments show a substantially random coiled secondary structure not affected by pH. The low-resolution model of Lmr-47 presented a prolate elongated shape at pH 8.0. Using the 3D structure obtained by molecular modeling, docking experiments identified five good and three suitable competitive inhibitors. Conclusion: Together, our work provided insights into the structure of the Lmr-47 and identified inhibitors that may enhance our understanding of thrombin-like family proteins.     

Fragment-based and classical quantitative structure–activity relationships for a series of hydrazides as antituberculosis agents

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. Multidrug-resistant Mycobacterium tuberculosis is an emerging problem of great importance to public health, and there is an urgent need for new anti-TB drugs. In the present work, classical 2D quantitative structure-activity relationships (QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 91 isoniazid derivatives. Significant statistical models (classical QSAR, q (2) = 0.68 and r (2) = 0.72; HQSAR, q (2) = 0.63 and r (2) = 0.86) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 24 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, [Formula: see text] ; classical QSAR, [Formula: see text]).     

A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer

Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.g., ⁶⁸Ga, ⁶⁴Cu, ¹⁷⁷Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (^99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, ^99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on ^99mTc outscores that of PET agents and ^99mTc-PSMA SPECT/CT may be a cost-effective alternative for ⁶⁸Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [^99mTc]Tc-tagged PSMA agents with particular attention to [^99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [⁶⁸Ga]Ga-PSMA11.     

Biodegradable Nanoparticles Loaded with Levodopa and Curcumin for Treatment of Parkinson’s Disease

Background: Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. Levodopa (L-DOPA) remains the gold-standard drug available for treating PD. Curcumin has many pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anti-amyloid, and antitumor properties. Copolymers composed of Poly (ethylene oxide) (PEO) and biodegradable polyesters such as Poly (ε-caprolactone) (PCL) can self-assemble into nanoparticles (NPs). This study describes the development of NH₂–PEO–PCL diblock copolymer positively charged and modified by adding glutathione (GSH) on the outer surface, resulting in a synergistic delivery of L-DOPA curcumin that would be able to pass the blood–brain barrier. Methods: The NH₂–PEO–PCL NPs suspensions were prepared by using a nanoprecipitation and solvent displacement method and coated with GSH. NPs were submitted to characterization assays. In order to ensure the bioavailability, Vero and PC12 cells were treated with various concentrations of the loaded and unloaded NPs to observe cytotoxicity. Results: NPs have successfully loaded L-DOPA and curcumin and were stable after freeze-drying, indicating advancing into in vitro toxicity testing. Vero and PC12 cells that were treated up to 72 h with various concentrations of L-DOPA and curcumin-loaded NP maintained high viability percentage, indicating that the NPs are biocompatible. Conclusions: NPs consisting of NH₂–PEO–PCL were characterized as potential formulations for brain delivery of L-DOPA and curcumin. The results also indicate that the developed biodegradable nanomicelles that were blood compatible presented low cytotoxicity.     

Potential Use of Tea Tree Oil as a Disinfectant Agent against Coronaviruses: A Combined Experimental and Simulation Study

The COVID-19 pandemic has highlighted the relevance of proper disinfection procedures and renewed interest in developing novel disinfectant materials as a preventive strategy to limit SARS-CoV-2 contamination. Given its widely known antibacterial, antifungal, and antiviral properties, Melaleuca alternifolia essential oil, also named Tea tree oil (TTO), is recognized as a potential effective and safe natural disinfectant agent. In particular, the proposed antiviral activity of TTO involves the inhibition of viral entry and fusion, interfering with the structural dynamics of the membrane and with the protein envelope components. In this study, for the first time, we demonstrated the virucidal effects of TTO against the feline coronavirus (FCoVII) and the human coronavirus OC43 (HCoV-OC43), both used as surrogate models for SARS-CoV-2. Then, to atomistically uncover the possible effects exerted by TTO compounds on the outer surface of the SARS-CoV-2 virion, we performed Gaussian accelerated Molecular Dynamics simulations of a SARS-CoV-2 envelope portion, including a complete model of the Spike glycoprotein in the absence or presence of the three main TTO compounds (terpinen-4-ol, γ-terpinene, and 1,8-cineole). The obtained results allowed us to hypothesize the mechanism of action of TTO and its possible use as an anti-coronavirus disinfectant agent.     

Double Hook Perylene Diimide as a New Receptor for PAHs: An Experimental and Theoretical Study

In a one-step reaction, we prepared a dibenzylamine perylene diimide derivative (PDI). Its double hook structure allows for self-association with a constant of K_d ∼10⁸ M⁻¹ determined by fluorescence. We confirmed its ability to bind PAHs using UV/Vis, fluorescence, and ¹H NMR titrations in CHCl₃. The complex formation signature in UV/vis is a new band at 567 nm. The calculated binding constants (K_a∼10⁴ M⁻¹) follow the trend pyrene>perylene>phenanthrene>naphthalene>anthracene. Theoretical modeling of these systems using DFT ωB97X-D/6-311G(d,p) proved helpful in rationalizing the complex formation and the observed association trend. The distinctive signal in UV/vis is due to a charge transfer in the complex from orbitals in the guest to the host. SAPT(DFT) confirmed that the driving forces in the complex formation are exchange and dispersion (π–π interactions). Still, the recognition ability depends on the electrostatic component of the interaction, a minor fraction.     

η3‐Benzyl‐Nickel‐Diimine Complex: Synthesis and Catalytic Properties in Ethylene Polymerization

The oxidative addition of benzyl chloride to Ni(cod)₂ in the presence of 1,4‐bis(2,6‐diisopropylphenyl)acenaphthenediimine followed by chloride abstraction affords [(η³‐CH₂C₆H₅)Ni(α‐diimine)][PF₆] (α‐diimine = 1,4‐bis(2,6‐diisopropylphenyl)acenaphthenediimine) in 70% yield. The complex is active in ethylene polymerization in the presence of methylaluminoxane and under mild reaction conditions. The polyethylenes obtained are highly branched, have very low densities, do not show T_m or measurable crystallinity and have molecular weights ranging from 80 × 10³ to 290 × 10³ g · mol⁻¹.