AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Antimony resistance in Leishmania (Viannia) braziliensis clinical isolates from atypical lesions associates with increased ARM56/ARM58 transcripts and reduced drug uptake.

Submitted by Nuzia Santos ([email protected]) on 2019-08-29T14:03:01Z No. of bitstreams: 1 Antimony resistance in Leishmania .pdf: 1634456 bytes, checksum: aef9a32186654027ee883cd5b35c81b1 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2019-08-29T14:08:25Z (GMT) No. of bitstreams: 1 Antimony resistance in Leishmania .pdf: 1634456 bytes, checksum: aef9a32186654027ee883cd5b35c81b1 (MD5)Made available in DSpace on 2019-08-29T14:08:25Z (GMT). No. of bitstreams: 1 Antimony resistance in Leishmania .pdf: 1634456 bytes, checksum: aef9a32186654027ee883cd5b35c81b1 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Instituto de Ciências Biológicas. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.BACKGROUND: In addition to the limited therapeutic arsenal and the side effects of antileishmanial agents, drug resistance hinders disease control. In Brazil, Leishmania braziliensis causes atypical (AT) tegumentary leishmaniasis lesions, frequently refractory to treatment. OBJECTIVES: The main goal of this study was to characterise antimony (Sb)-resistant (SbR) L. braziliensis strains obtained from patients living in Xakriabá indigenous community, Minas Gerais, Brazil. METHODS: The aquaglyceroporin 1-encoding gene (AQP1) from L. braziliensis clinical isolates was sequenced, and its function was evaluated by hypo-osmotic shock. mRNA levels of genes associated with Sb resistance were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Atomic absorption was used to measure Sb uptake. FINDINGS: Although clinical isolates presented delayed recovery time in hypo-osmotic shock, AQP1 function was maintained. Isolate 340 accumulated less Sb than all other isolates, supporting the 65-fold downregulation of AQP1 mRNA levels. Both 330 and 340 isolates upregulated antimony resistance marker (ARM) 56/ARM58 and multidrug resistant protein A (MRPA); however, only ARM58 upregulation was an exclusive feature of SbR field isolates. CA7AE seemed to increase drug uptake in L. braziliensis and represented a tool to study the role of glycoconjugates in Sb transport. MAIN CONCLUSIONS: There is a clear correlation between ARM56/58 upregulation and Sb resistance in AT-harbouring patients, suggesting the use of these markers as potential indicators to help the treatment choice and outcome, preventing therapeutic failure

First report of the <i>in vitro</i> antileishmanial properties of extremophile plants from the Algarve Coast

<p>This work reports for the first time the <i>in vitro</i> anti <i>Leishmania infantum</i> activity of acetone and dichloromethane (DCM) extracts from 25 extremophile plants from Southern Portugal. DCM extracts from <i>Inula chritmoides</i> and <i>Spergularia rubra</i> were active against axenic promastigotes and intracellular amastigotes, had anti-inflammatory properties on lipopolysaccharide (LPS)-stimulated macrophages, inhibited acetylcholinesterase and had no haemolytic activity on human erythrocytes. Eleven phenolics were identified by high-performance liquid chromatography with diode-array detection (HPLC-DAD) in <i>I. crithmoides</i> and one phenolic in <i>S. rubra</i>. Isolation and identification of the active molecules is in progress.</p

Comparison of diagnostic performance of RT-qPCR, RT-LAMP and IgM/IgG rapid tests for detection of SARS-CoV-2 among healthcare workers in Brazil

Background: COVID-19 has become a major public health problem after the outbreak caused by SARS-CoV-2 virus. Great efforts to contain COVID-19 transmission have been applied worldwide. In this context, accurate and fast diagnosis is essential. Methods: In this prospective study, we evaluated the clinical performance of three different RNA-based molecular tests – RT-qPCR (Charité protocol), RT-qPCR (CDC (USA) protocol) and RT-LAMP – and one rapid test for detecting anti-SARS-CoV-2 IgM and IgG antibodies. Results: Our results demonstrate that RT-qPCR using the CDC (USA) protocol is the most accurate diagnostic test among those evaluated, while oro-nasopharyngeal swabs are the most appropriate biological sample. RT-LAMP was the RNA-based molecular test with lowest sensitivity while the serological test presented the lowest sensitivity among all evaluated tests, indicating that the latter test is not a good predictor of disease in the first days after symptoms onset. Additionally, we observed higher viral load in individuals who reported more than 3 symptoms at the baseline. Nevertheless, viral load had not impacted the probability of testing positive for SARS-CoV-2. Conclusion: Our data indicates that RT-qPCR using the CDC (USA) protocol in oro-nasopharyngeal swabs samples should be the method of choice to diagnosis COVID-19