CATMoS: Collaborative Acute Toxicity Modeling Suite.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495

Strategies of Virtual Screening in Medicinal Chemistry

Virtual screening represents an effective computational strategy to rise-up the chances of finding new bioactive compounds by accelerating the time needed to move from an initial intuition to market. Classically, the most pursued approaches rely on ligand- and structure-based studies, the former employed when structural data information about the target is missing while the latter employed when X-ray/NMR solved or homology models are instead available for the target. The authors will focus on the most advanced techniques applied in this area. In particular, they will survey the key concepts of virtual screening by discussing how to properly select chemical libraries, how to make database curation, how to applying and- and structure-based techniques, how to wisely use post-processing methods. Emphasis will be also given to the most meaningful databases used in VS protocols. For the ease of discussion several examples will be presented.</p

Persulfate Reaction in a Hair-Bleaching Formula: Unveiling the Unconventional Reactivity of 1,13-Diamino-4,7,10-Trioxatridecane

The stability and unconventional reactivity of 1,13-diamino-4,7,10-trioxatridecane in the presence of NH3, H2O2, and (NH4)2S2O8are described. The ether-diamine is an ingredient marketed to hair salons and consumers for so-called "plex" services to compensate for hair damage during bleaching. The main reaction product identified is an unexpected azanyl ester derivative. This is considered relevant for the safety evaluation when used in cosmetic products. The mechanism of reaction was explored through DFT calculations. This study represents the first attempt to assess the stability of a plex active in an oxidative environment

Accuracy of transvaginal sonography and contrast-enhanced magnetic resonance-colonography for the presurgical staging of deep infiltrating endometriosis.

bjective To investigate the accuracy of transvaginal sonography (TVS) and contrast-enhanced magnetic resonance-colonography (CE-MR-C) for the presurgical assessment of deep infiltrating endometriosis (DIE). Methods Ninety women were enrolled prospectively for suspicion of DIE. All patients underwent TVS and CE-MR-C, with each operator blinded to the results of the other exam, before laparoscopy. The sites of DIE examined by both imaging techniques were: rectovaginal septum, pouch of Douglas, uterosacral ligaments, vesicouterine pouch, bowel, bladder and vagina. The presence of adhesions and the involvement of adnexa and of a previous abdominal scar, when there was clinical suspicion, were also evaluated. TVS and CEMR- C findings were compared with laparoscopic and histological results. Results Endometriosis was confirmed by laparoscopy in 95.6% (86/90) of cases. In 82.2% (74/90) of patients there was DIE. The global accuracy for TVS in the detection of DIE was 89.2%, sensitivity was 81.1%, specificity was 94.2%, positive predictive value was 89.6%, negative predictive value was 89.0%, the positive likelihood ratio was 13.9 and the negative likelihood ratio was 0.2. For CE-MR-C, these values were 87.2%, 71.1%, 97.1%, 93.7%, 84.6%, 24.4 and 0.3, respectively. CE-MR-C allowed diagnosis of all cases of bowel involvement; the accuracy for infiltration and stenosis was 100%. The accuracy of TVS for rectosigmoid nodules was 91.1% and that for infiltration was 88.9%. Conclusions Both TVS and CE-MR-C showed satisfactory results for the presurgical assessment of DIE. TVS appears to be a powerful, simple, feasible, cost-effective tool for preoperative staging of DIE. CE-MR-C is an .X-ray free' technique, which could be reserved for cases with deep infiltrating rectosigmoid lesions and for the prediction of stenosis and involvement of the upper part of the colon and small intestine

Controlling the Binding Efficiency of Surface Confined Antibodies through the Design of Mixed Self‐Assembled Monolayers

Abstract A plethora of different electronic and optoelectronic devices have been developed lately, for biosensing applications (e.g., label‐free, fast, and easier to operate) based on a detecting interface accommodating the biorecognition elements, anchored by thiolate self‐assembled monolayers (SAMs) on a gold surface. Here, a surface plasmon resonance (SPR) characterization of anti‐p24 anchored on different SAMs is performed to investigate the effect of the SAM structure on the antibodies’ packing efficiency and the sensors’ analytical figures of merit. Notably, the mixed SAM deposited from a solution 10:1 of 3‐mercaptopropionic acid and 11‐mercaptoundecanoic acid (11MUA) is compared to that resulting from a solution 10:1 of ad hoc synthesized N‐(2‐hydroxyethyl)‐3‐mercaptopropanamide (NMPA)/11MUA. Despite the improvement in the anti‐p24 surface coverage registered using the 11MUA/NMPA SAM, the latter produces a significant decrease in the antibodies’ binding efficiency against human immunodeficiency virus p24 protein. To provide a molecular rationale behind the SPR data, density functional theory calculations are also undertaken. A comprehensive physical view of the main competing phenomena affecting the biorecognition events at a biofunctionalized gold detecting interface is represented here

Multi-sulfonated ligands on gold nanoparticles as virucidal antiviral for Dengue virus

Dengue virus (DENV) causes 390 million infections per year. Infections can be asymptomatic or range from mild fever to severe haemorrhagic fever and shock syndrome. Currently, no effective antivirals or safe universal vaccine is available. In the present work we tested different gold nanoparticles (AuNP) coated with ligands omega-terminated with sugars bearing multiple sulfonate groups. We aimed to identify compounds with antiviral properties due to irreversible (virucidal) rather than reversible (virustatic) inhibition. The ligands varied in length, in number of sulfonated groups as well as their spatial orientation induced by the sugar head groups. We identified two candidates, a glucose- and a lactose-based ligand showing a low EC50 (effective concentration that inhibit 50% of the viral activity) for DENV-2 inhibition, moderate toxicity and a virucidal effect in hepatocytes with titre reduction of Median Tissue Culture Infectious Dose log(10)TCID(50) 2.5 and 3.1. Molecular docking simulations complemented the experimental findings suggesting a molecular rationale behind the binding between sulfonated head groups and DENV-2 envelope protein

Targeting Siderophore-Mediated Iron Uptake in <i>M. abscessus</i>: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 ≈ 5 µM). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives

17β-Hydroxysteroid Dehydrogenase Type 1 Inhibition: A Potential Treatment Option for Non-Small Cell Lung Cancer.

In the face of the clinical challenge posed by non-small cell lung cancer (NSCLC), the present need for new therapeutic approaches is genuine. Up to now, no proof existed that 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a viable target for treating this disease. Synthesis of a rationally designed library of 2,5-disubstituted furan derivatives followed by biological screening led to the discovery of 17β-HSD1 inhibitor 1, capable of fully inhibiting human NSCLC Calu-1 cell proliferation. Its pharmacological profile renders it eligible for further in vivo studies. The very high selectivity of 1 over 17β-HSD2 was investigated, revealing a rational approach for the design of selective inhibitors. 17β-HSD1 and 1 hold promise in fighting NSCLC

Targeting Siderophore-Mediated Iron Uptake in M. abscessus: A New Strategy to Limit the Virulence of Non-Tuberculous Mycobacteria

Targeting pathogenic mechanisms, rather than essential processes, represents a very attractive approach for the development of new antimycobacterial drugs. In this context, iron acquisition routes have recently emerged as potentially druggable pathways. However, the importance of siderophore biosynthesis in the virulence and pathogenicity of M. abscessus (Mab) is still poorly understood. In this study, we investigated the Salicylate Synthase (SaS) of Mab as an innovative molecular target for the development of inhibitors of siderophore production. Notably, Mab-SaS does not have any counterpart in human cells, making it an interesting candidate for drug discovery. Starting from the analysis of the binding of a series of furan-based derivatives, previously identified by our group as inhibitors of MbtI from M. tuberculosis (Mtb), we successfully selected the lead compound 1, exhibiting a strong activity against Mab-SaS (IC50 &asymp; 5 &micro;M). Computational studies characterized the key interactions between 1 and the enzyme, highlighting the important roles of Y387, G421, and K207, the latter being one of the residues involved in the first step of the catalytic reaction. These results support the hypothesis that 5-phenylfuran-2-carboxylic acids are also a promising class of Mab-SaS inhibitors, paving the way for the optimization and rational design of more potent derivatives