Structure-Guided Computational Approaches to Unravel Druggable Proteomic Landscape of Mycobacterium leprae.

Leprosy, caused by Mycobacterium leprae (M. leprae), is treated with a multidrug regimen comprising Dapsone, Rifampicin, and Clofazimine. These drugs exhibit bacteriostatic, bactericidal and anti-inflammatory properties, respectively, and control the dissemination of infection in the host. However, the current treatment is not cost-effective, does not favor patient compliance due to its long duration (12 months) and does not protect against the incumbent nerve damage, which is a severe leprosy complication. The chronic infectious peripheral neuropathy associated with the disease is primarily due to the bacterial components infiltrating the Schwann cells that protect neuronal axons, thereby inducing a demyelinating phenotype. There is a need to discover novel/repurposed drugs that can act as short duration and effective alternatives to the existing treatment regimens, preventing nerve damage and consequent disability associated with the disease. Mycobacterium leprae is an obligate pathogen resulting in experimental intractability to cultivate the bacillus in vitro and limiting drug discovery efforts to repositioning screens in mouse footpad models. The dearth of knowledge related to structural proteomics of M. leprae, coupled with emerging antimicrobial resistance to all the three drugs in the multidrug therapy, poses a need for concerted novel drug discovery efforts. A comprehensive understanding of the proteomic landscape of M. leprae is indispensable to unravel druggable targets that are essential for bacterial survival and predilection of human neuronal Schwann cells. Of the 1,614 protein-coding genes in the genome of M. leprae, only 17 protein structures are available in the Protein Data Bank. In this review, we discussed efforts made to model the proteome of M. leprae using a suite of software for protein modeling that has been developed in the Blundell laboratory. Precise template selection by employing sequence-structure homology recognition software, multi-template modeling of the monomeric models and accurate quality assessment are the hallmarks of the modeling process. Tools that map interfaces and enable building of homo-oligomers are discussed in the context of interface stability. Other software is described to determine the druggable proteome by using information related to the chokepoint analysis of the metabolic pathways, gene essentiality, homology to human proteins, functional sites, druggable pockets and fragment hotspot maps

Computational drug discovery for the Zika virus

Few Zika virus (ZIKV) outbreaks had been reported since its first detection in 1947, until the recent epidemics occurred in South America (2014/2015) and expeditiously became a global public health emergency. This arbovirus reached 0.5-1.3 million cases of ZIKV infection in Brazil in 2015 and rapidly spread in new geographic areas such as the Americas. Despite the mild symptoms of the Zika fever, the major concern is related to the related severe neurological disorders, especially microcephaly in newborns. Advances in ZIKV drug discovery have been made recently and constitute promising approaches to ZIKV treatment. In this review, we summarize current computational drug discovery efforts and their applicability to discovery of anti-ZIKV drugs. Lastly, we present successful examples of the use of computational approaches to ZIKV drug discovery

The Molecular Organization of Human cGMP Specific Phosphodiesterase 6 (PDE6): Structural Implications of Somatic Mutations in Cancer and Retinitis Pigmentosa.

In the cyclic guanosine monophosphate (cGMP) signaling pathway, phosphodiesterase 6 (PDE6) maintains a critical balance of the intracellular concentration of cGMP by catalyzing it to 5' guanosine monophosphate (5'-GMP). To gain insight into the mechanistic impacts of the PDE6 somatic mutations that are implicated in cancer and retinitis pigmentosa, we first defined the structure and organization of the human PDE6 heterodimer using computational comparative modelling. Each subunit of PDE6αβ possesses three domains connected through long α-helices. The heterodimer model indicates that the two chains are likely related by a pseudo two-fold axis. The N-terminal region of each subunit is comprised of two allosteric cGMP-binding domains (Gaf-A & Gaf-B), oriented in the same way and interacting with the catalytic domain present at the C-terminal in a way that would allow the allosteric cGMP-binding domains to influence catalytic activity. Subsequently, we applied an integrated knowledge-driven in silico mutation analysis approach to understand the structural and functional implications of experimentally identified mutations that cause various cancers and retinitis pigmentosa, as well as computational saturation mutagenesis of the dimer interface and cGMP-binding residues of both Gaf-A, and the catalytic domains. We studied the impact of mutations on the stability of PDE6αβ structure, subunit-interfaces and Gaf-cGMP interactions. Further, we discussed the changes in interatomic interactions of mutations that are destabilizing in Gaf-A (R93L, V141 M, F162 L), catalytic domain (D600N, F742 L, F776 L) and at the dimer interface (F426A, F248G, F424 N). This study establishes a possible link of change in PDE6αβ structural stability to the experimentally observed disease phenotypes

Erratum to: The study of cardiovascular risk in adolescents – ERICA: rationale, design and sample characteristics of a national survey examining cardiovascular risk factor profile in Brazilian adolescents

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Evidências sobre o uso de leite materno no tratamento dermatológico da pele do recém-nascido: Evidence on the use of breast milk in the dermatological treatment of newborn skin

O presente estudo tem como objetivo analisar as evidências sobre o uso de leite materno no tratamento dermatológico da pele do recém-nascido. A pesquisa foi desenvolvida com base em uma Revisão Sistemática da Literatura (RSL). A pesquisa foi realizada na Biblioteca Virtual do Ministério da Saúde (BVS) que indexa artigos de diferentes bases de dados como Scielo, Lilacs e MedLine e na PubMed.  Como critérios de inclusão foi considerado ser disponível em formato completo e publicado nos últimos dez anos (2012-2022). Foram excluídos estudos que não respondessem o tema de pesquisa ou que estivessem duplicados nas bases de dados. O uso do leite materno como tratamento dermatológico de pele é potencial, porém, os estudos ainda são escassos e inconclusivos, fazendo-se importante que estudos sejam realizados para que se possa sanar dúvidas sobre o uso do leite materno, considerando ser um tratamento natural e de baixo custo

High levels of immunosuppression are related to unfavourable outcomes in hospitalised patients with rheumatic diseases and COVID-19 : first results of ReumaCoV Brasil registry

Objectives To evaluate risk factors associated with unfavourable outcomes: emergency care, hospitalisation, admission to intensive care unit (ICU), mechanical ventilation and death in patients with immune-mediated rheumatic disease (IMRD) and COVID-19. Methods Analysis of the first 8 weeks of observational multicentre prospective cohort study (ReumaCoV Brasil register). Patients with IMRD and COVID-19 according to the Ministry of Health criteria were classified as eligible for the study. Results 334 participants were enrolled, a majority of them women, with a median age of 45 years; systemic lupus erythematosus (32.9%) was the most frequent IMRD. Emergency care was required in 160 patients, 33.0% were hospitalised, 15.0% were admitted to the ICU and 10.5% underwent mechanical ventilation; 28 patients (8.4%) died. In the multivariate adjustment model for emergency care, diabetes (prevalence ratio, PR 1.38; 95% CI 1.11 to 1.73; p=0.004), kidney disease (PR 1.36; 95% CI 1.05 to 1.77; p=0.020), oral glucocorticoids (GC) (PR 1.49; 95% CI 1.21 to 1.85; p50 years (PR 1.89; 95% CI 1.26 to 2.85; p=0.002), no use of tumour necrosis factor inhibitor (TNFi) (PR 2.51;95% CI 1.16 to 5.45; p=0.004) and methylprednisolone pulse therapy (PR 2.50; 95% CI 1.59 to 3.92; p<0.001); for ICU admission, oral GC (PR 2.24; 95% CI 1.36 to 3.71; p<0.001) and pulse therapy with methylprednisolone (PR 1.65; 95% CI 1.00 to 2.68; p<0.043); the two variables associated with death were pulse therapy with methylprednisolone or cyclophosphamide (PR 2.86; 95% CI 1.59 to 5.14; p<0.018). Conclusions Age >50 years and immunosuppression with GC and cyclophosphamide were associated with unfavourable outcomes of COVID-19. Treatment with TNFi may have been protective, perhaps leading to the COVID-19 inflammatory process

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

Submitted by Sandra Infurna ([email protected]) on 2018-02-20T11:41:47Z No. of bitstreams: 1 floriano_silvajr_etal_IOC_2017.pdf: 4853576 bytes, checksum: c4a6d220b4f1fda0f3baed6891cad266 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-02-20T11:54:05Z (GMT) No. of bitstreams: 1 floriano_silvajr_etal_IOC_2017.pdf: 4853576 bytes, checksum: c4a6d220b4f1fda0f3baed6891cad266 (MD5)Made available in DSpace on 2018-02-20T11:54:05Z (GMT). No. of bitstreams: 1 floriano_silvajr_etal_IOC_2017.pdf: 4853576 bytes, checksum: c4a6d220b4f1fda0f3baed6891cad266 (MD5) Previous issue date: 2017Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Modelagem Molecular e QSAR. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Modelagem Molecular e QSAR. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Modelagem e Dinâmica Molecular. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Metrologia Qualidade e Tecnologia. Diretoria de Metrologia Aplicada às Ciências da Vida. Programa de Biotecnologia. Duque de Caxias, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Modelagem e Dinâmica Molecular. Rio de Janeiro, RJ, Brasil.Universidade de São Paulo., Departamento de Fisiologia. São Paulo, SP, Brasil.Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Química. Laboratório de Síntese Orgânica e Prospecção Biológica. Rio de Janeiro, RJ, Brasil.Fundação oOswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ, Brasil.Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding

Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling

BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Qo site of P. falciparum cytochrome bc1 complex (Pfbc1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Qo site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite