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Identification of potential molecular targets related to cancer for the formicamycin’s family

Identification of potential molecular targets related to cancer for the formicamycin’s family

Bruna Schuck de Azevedo and Rafael Andrade Caceres

According to the Global Cancer Observatory, 18 million new cases and 9.5 million deaths were estimated for all types of cancer in 2018. The World Health Organization predicts that in 2030 there will be a 70% increase in new cases and 45% in deaths. Due to the rise of cancer incidence and mortality, it is necessary to invest in the discovery and development of new antineoplastic drugs. The novel family of molecules called formicamycin, active against some antibiotic-resistant microorganisms, had a tyrosine kinase enzyme predicted as one of its molecular targets. As this enzyme plays a role in the progression of cancer, the potential antineoplastic action of the formicamycins has been studied. In order to identify the potential molecular targets for an antineoplastic action of the compounds of the formicamycin family, a reverse virtual screening (RVS) was performed using two web servers, PharmMapper and SwissTargetPrediction, to establish the potential targets which interact with them. The targets obtained concomitantly on both servers had their influence on carcinogenesis verified through a literature review in PubMed. The binding energy between target and compound was determined for the targets that seemed to influence carcinogenesis through simulations of molecular docking, with Autodock 4.2 and Autodock Vina, and molecular dynamics, with the GROMACS v.4.6.7 package. Fifteen potential molecular targets were obtained at the intersection of the two RVS servers used. In the literary review, twelve of them were associated with carcinogenesis. These twelve molecular targets were subjected to molecular docking and molecular dynamics simulations. At the end of the RVS process, three potential molecular targets for the formicamycins were identified. Among these macromolecules, nuclear receptor subfamily 1 group I member 2 and matrix metalloproteinase 3 are the most promising targets for an antineoplastic action of these compounds.

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PROSPECTION OF PROTEIN CANDIDATES FOR DRUG AND VACCINE DEVELOPMENT AGAINST STREPTOCOCCUS PNEUMONIAE INFECTIONS

PROSPECTION OF PROTEIN CANDIDATES FOR DRUG AND VACCINE DEVELOPMENT AGAINST STREPTOCOCCUS PNEUMONIAE INFECTIONS

Igor Oliveira, Sarah Souza and Bernardo Santos

Streptococcus pneumoniae is a Gram-positive bacterium and the etiological agent of many diseases related to the respiratory tract (such as pneumonia), meningitis and middle ear infections. The increase in hospitalization rates resulting from pneumococcal infections and the growing reports on antibiotic-resistant pneumococcal strains lead to the development of new prophylactic and treatment methods. In this work, the subtractive genomics and reverse vaccinology approaches were considered to screen protein targets for the development of drug and vaccine against S. pneumoniae infections. The sequences of 63 complete genomes were retrieved from the NCBI database and processed for the identification of orthologous proteins encoded by all strains using OrthoFinder. The core proteome found to be not homologous to Homo sapiens comprised 287 proteins, of which 112 were predicted to be exported by S. pneumoniae and 160 were classified as cytoplasmic proteins by SurfG. As the exported bacterial proteins most likely interact with the host’s immune system, we used Vaxign to evaluate the affinity of these proteins for the histocompatibility complex (MHC). This analysis revealed 6 immunogenic proteins with great potential use in subunit vaccine development. In addition, we obtained good quality three-dimensional structure models for 33 cytoplasmic proteins using the MHOLline workflow. Among the modeled proteins, 4 drug target candidates were found using the PBIT pipeline. This selection was made according to the involvement of protein in virulence and essentiality in bacteria, and the absence of homology with proteins present in the human intestinal microbiota. These candidates will be considered for molecular docking with a library of 5,000 natural plant compounds using AutoDock Vina. The present work brings up new perspectives to control the emerging and worldwide distributed S. pneumoniae infections in human.

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PREDICTION OF PROTEIN CANDIDATES FOR DRUG AND VACCINE DEVELOPMENT AGAINST PSEUDOMONAS AERUGINOSA INFECTIONS

PREDICTION OF PROTEIN CANDIDATES FOR DRUG AND VACCINE DEVELOPMENT AGAINST PSEUDOMONAS AERUGINOSA INFECTIONS

Sarah Souza, Igor Oliveira and Letícia Carvalho

Pseudomonas aeruginosa is a Gram-negative bacterium widely distributed in the environment. As an opportunistic pathogen, P. aeruginosa is associated with high morbidity and mortality in immunocompromised patients worldwide, especially those already affected by cystic fibrosis. Its extensive resistance to antimicrobials and the lack of an effective vaccine leads to an urgency in searching for new therapeutic options. The present work aimed to use the subtractive genomics and
reverse vaccinology approaches for the screening of protein targets to develop drug and vaccine against P. aeruginosa. The sequences of 174 complete genomes were retrieved from the NCBI database and processed for the identification of orthologous proteins encoded by all strains using OrthoFinder. The core proteome found to be not homologous to the human host comprised 695 proteins, of which 385 were predicted as cytoplasmic proteins and 310 as proteins exported by P. aeruginosa according to SurfG. We were able to obtain good quality three -dimensional structure models for 71 cytoplasmic proteins using the MHOLline workflow. Among the modeled proteins, 5 best drug target candidates were found using the PBIT pipeline. This selection was made according to the
involvement of protein in virulence and essentiality in bacteria, besides the absence of homology with proteins produced by the intestinal microbiota in human. Using Vaxign, 44 candidate antigens were found among the proteins exported by P. aeruginosa, of which 7 presented greater potential for the development of subunit vaccines. Next, the drug target candidates will be used for molecular docking
with a library of 5,000 natural plant compounds using AutoDock Vina. Also, immunoinformatic approaches will be considered to select the best antigen epitopes for the formulation of a chimeric subunit vaccine. This work brings up

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Interactome of Corynebacterium ulcerans toxigenic strains reveals hub proteins being potential drug targets

Interactome of Corynebacterium ulcerans toxigenic strains reveals hub proteins being potential drug targets

Gustavo Andrew Mahon Mendes Pereira, Luis Felipe de Morais Melo, Luis Carlos Guimarães, Vasco Ariston de Carvalho Azevedo and Edson Luiz Folador

Corynebacterium ulcerans has toxigenic strains that produce the diphtheria toxin similar to C. diphtheriae. Among the bacteria causing diphtheria, C. ulcerans has a greater mutagenic potential because it has both humans and animals as reservoirs. Being reemergent, there was an increase in cases even in immunized countries, requiring new approaches for new drug targets selection. Applying the interolog mapping method we map interactions with confidence score >= 700 from 5090 STRING database organisms, generating the protein-protein interaction network and identifying 22,347 interactions conserved in 10 toxigenic C. ulcerans strains. Selecting by highest degree interaction, 457 hub proteins were identified, 421 (92.12%) of them have the essentiality validated by homology in the Database of Essential Genes (DEG) and 36 (7.88%) were considered essential after functional and enrichment analysis. The Clusters of Orthologous Groups (COG) analysis highlighted the more representative groups: “Translation, ribosomal structure and biogenesis (J)” (74%), “Amino acid transport and metabolism (E)” (13.96%), “Replication, recombination and repair (L)” (8.21%) and only 5.34% “Function Unknown (S)” composed mostly of hypothetical proteins. The Gene Ontology (GO) enrichment analysis identified the most significant biological processes (p>0.95): “Cell redox homeostasis”, “DNA recombination”, “Cell wall organization”, “SOS response”, among others. Aiming to select targets do not favoring toxicity, we identified 351 (76.8%) non-host homologous hub proteins, some having higher degree interaction are: “Inosine 5-monophosphate dehydrogenase” (195, CulFRC58_1614), “Protein RecA” (182, recA), “DNA-directed RNA polymerase subunit alpha” (165, rpoA), “2-oxoglutarate dehydrogenase E1 component” (156, odhA) and “DNA-directed RNA polymerase subunit beta” (154, rpoB). All non-host homologous hub proteins possess potential for drug targets and are useful to evaluate the affinity of candidate compounds, experimentally or, similarly that our group performed in-silico affinity test against unpublished synthetic derivatives of tetraisoquinoline alkaloids.