Design of N-11-Azaartemisinins Potentially Active against Plasmodium falciparum by Combined Molecular Electrostatic Potential, Ligand-Receptor Interaction and Models Built with Supervised Machine Learning Methods

N-11-azaartemisinins potentially active against Plasmodium falciparum are designed by combining molecular electrostatic potential (MEP), ligand-receptor interaction, and models built with supervised machine learning methods (PCA, HCA, KNN, SIMCA, and SDA). The optimization of molecular structures was performed using the B3LYP/6-31G* approach. MEP maps and ligand-receptor interactions were used to investigate key structural features required for biological activities and likely interactions between N-11-azaartemisinins and heme, respectively. The supervised machine learning methods allowed the separation of the investigated compounds into two classes: cha and cla, with the properties εLUMO+1 (one level above lowest unoccupied molecular orbital energy), d(C6-C5) (distance between C6 and C5 atoms in ligands), and TSA (total surface area) responsible for the classification. The insights extracted from the investigation developed and the chemical intuition enabled the design of sixteen new N-11-azaartemisinins (prediction set), moreover, models built with supervised machine learning methods were applied to this prediction set. The result of this application showed twelve new promising N-11-azaartemisinins for synthesis and biological evaluation.

Polymorphisms of the Toll-Like Receptor-2 Gene in Patients with Leprosy and Their Healthy Contacts

Leprosy is an immunopathology caused by M. leprae;its evolution depends on immunological and genetic aspects of the host. The objective was verifying the relationship between SNPs 2029 and 2258 of the TLR-2 gene and leprosy. Blood samples from 127 individuals were analyzed: 45 patients, being 34 multibacillary (MB) and 11 paucibacillary (PB) and 82 contacts, in the municipalities of the State of Pará-Brazil. SNPs 2029 and 2258 of the TLR-2 gene were genotyped by sequencing on the ABI 3130 Genetic Analyzer (Applied Biosystems), analyzed using Fisher’s exact test. Distribution of SNP 2029 genotypes: all MB individuals presented the C/C genotype and the mutant (C/T) genotype was observed in contacts and PB. Alleles: all MB individuals presented only C allele and the mutant allele (T) was observed in contacts and PB. SNP 2258 genotypes: 79 contacts had G/G genotype and only 3 had G/A genotype, the MB group had only G/G genotype and the PB group was predominant G/G, with only 1 G/A genotype. Alleles: all MB individuals had allele G and the mutant allele (A) was observed in contacts and PB. The association between the SNPs and the susceptibility or protection to leprosy was not observed.

Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-Heme Interaction and Multivariate Models

Artemisinins tested against W-2 strains of malaria falciparum are investigated with molecular electrostatic potential (MEP), in an attempt to identify key features of the compounds that are necessary for their activities, as well as to investigate likely interactions with the receptor in a biological process and to use that information to propose new molecules. In order to discover the best geometry involving the ligand-receptor complexes (heme) studied and help in the proposition of the new derivatives, molecular simulations of interactions between the most negative charged region around the peroxide and heme locates (the ones around the Fe2+ ion) were carried out. In addition, PCA (principal components analysis), HCA (hierarchical cluster analysis), SDA (stepwise discriminant analysis), and KNN (K-nearest neighbor) multivariate models were employed to investigate which descriptors are responsible for the classification between the higher and lower antimalarial activity of the compounds, and also this information was used to propose new potentially active molecules. The information accumulated in studies of MEP, molecular docking, and multivariate analysis supported the proposal of new structures with potential antimalarial activities. The multivariate models constructed were applied to the new structures and indicated numbers 19 and 20 as the most prominent for syntheses and biological assays.

Clinical and Spatial Characteristics of Severe Acute Respiratory Syndrome by COVID-19 in Indigenous of Brazil

The new coronavirus (SARS-CoV-2) broke out in Wuhan in China in December 2019, causing severe pneumonia and deaths, soon in March 2020, it reached pandemic level, affecting several countries including Brazil. The disease was named COVID-19, with characteristics of most infected having mild and moderate symptoms and a part severe symptom. The disease has already reached 158 ethnic groups, which have high vulnerability and limited access to health services. The objective is to investigate the clinical and spatial characteristics of Severe Acute Respiratory Syndrome of COVID-19 in the indigenous peoples of Brazil. It is an epidemiological, cross-sectional, analytical ecological study, based on data from the OpenDataSUS platform from 01/01/2020 to 31/08/2020. Profile variables, signs and symptoms and risk factors/comorbidities. The data were analyzed by Bioestat 5.3. There were 1,207 cases and 470 deaths. Profile: male gender (59.48%) means age 53 years. Signs and symptoms: fever (74.23%), cough (77.71%), sore throat (35.62%), dyspnea (69.34%), respiratory discomfort (62.80%), O2 saturation < 95% (56.42%);and associated with mortality: dyspnea (80.0%) and O2 saturation < 95% (69.36%). Risk factors and comorbidities (45.89%) were associated with deaths (54.04%). About comorbidities, chronic cardiovascular diseases represented (18.97%) and Diabetes Mellitus (18.97%), and associated with deaths: Chronic Cardiovascular Disease (24.46%). Being admitted to the ICU has a risk of death in (OR-3.96- < 0.0001-CI-2913/5383) followed by not being vaccinated against influenza (OR-1.85- < 0.0001-CI-1358/2528). The public and health policies of Brazil should be directed to control the dissemination of COVID-19 in this population, that COVID-19 evolves in the same intensity, however, the indigenous have vulnerabilities that can increase the impact of the pandemic in this population.

Persistence of Anti-SARS-CoV-2 IgM Antibody up to 8 Months Post-COVID-19

Here, we present a longitudinal analysis of two patients who recovered from COVID-19 more than 8 months prior but showed persistent serological detection of anti-SARS-CoV-2 IgM. We still do not know the exact reason for this prolonged persistence of IgM in these patients. To our knowledge, these are the first reports of IgM persistence in the context of SARS-CoV-2 infection and point to the need for no longer using IgM as a diagnostic criterion for acute or recent COVID-19. One should opt for gold standard molecular methodologies due to their high sensitivity and specificity.