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The HGPRT AND XPRT ENZYMES FROM Leishmania donovani: MOLECULAR MODELING AND STUDY OF DUAL INHIBITORS.

The HGPRT AND XPRT ENZYMES FROM Leishmania donovani: MOLECULAR MODELING AND STUDY OF DUAL INHIBITORS.

Lucas Sousa Palmeira and Bruno Silva Andrade

Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) and Xanthine Phosphoribosyltransferase (XPRT) are classified in the type I PRTases family, which are responsible for purine recycling in the organism to which they belong. Protozoans of the order Kinetoplastidae such as Leishmania spp. cannot make de novo purine synthesis, and they have only the recovery route. The aim of this work was to perform molecular homology modeling of both HGPRT and XPRT targets, as well as to perform a virtual screening in order to search dual inhibitor for both enzymes. The 3D structures of HGPRT and XPRT from Leishmania donovani (Laveran and Mesnil, 1903) were constructed by the Swiss-Model Workspace, considering the best available crystallographic templates for both targets. The ROCS program (Openeye Scientific Software) was used to develop five pharmacophore structures, which were based on five active compounds for type I PRTases. Then, we submitted the pharmacophore structures to a ROCS searching a database of 57,000 compounds from natural sources extracted from ZINC DATABASE, in which a total number of 1,825 compounds (hits) for the five pharmacophores were returned. In a second step, we performed a receptor-based virtual screening (RVBS) using AutoDock Vina for molecular docking calculations. The 50 best compounds for both enzymes obtained affinity energies between -8.4 and -10.9 Kcal/mol, of which ZINC4096947, ZINC519733, ZINC485610, ZINC2150030 and ZINC58116 presented best values for both enzymes, as well as Lipinski’s rule of five characteristics. Molecular dynamics calculations revealed that the compound ZINC2150030 remained within the active site of both enzymes after 50 ns. Additionally, this inhibitor candidate can be tested in vitro and in vivo as a new treatment option for leishmaniasis.

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In silico approaches for Mycoplasma pneumoniae multi-epitope vaccine construction

In silico approaches for Mycoplasma pneumoniae multi-epitope vaccine construction

Thaís Cristina Vilela Rodrigues, Sandeep Tiwari, Vasco Ariston de Carvalho Azevedo, Rodrigo Bentes Kato, Stephane Fraga de Oliveira Tosta and Siomar de Castro Soares

Pneumonia is a serious health problem with global effects, being the death cause of over one million people annually. Among the main microorganisms responsible by pneumonia, Mycoplasma pneumoniae is one of the most common, with a significant increase in the last years. The vaccines are fundamental in diseases prevention besides to considerably avoid the need of health services and funding resources. In this way, the proposal of the present study is to construct through immunoinformatic tools, a multi-epitope vaccine against M. pneumoniae. Multi-epitope vaccines are constituted by epitopes properly selected to induce targeted immune responses and avoid adverse reactions. First the core proteins were previously determined through reverse vaccinology, then the search for MHCI, MHCII and B epitopes were performed as well as the check for overlapping epitopes, capable to induce both humoral and cellular responses. Those epitopes were filtered according to their immunogenicity, population coverage, among others. The final epitopes were joined with heat-labile enterotoxin from Escherichia coli as adjuvant and the structure of the vaccine was predicted. The vaccine was considered physically stable, non-toxic, non-allergen, not significantly similar to human proteome and with appropriate antigenic and immunogenic properties. The molecular docking of the vaccine with the Toll-Like Receptor 2 was performed as well as the dynamic simulation to ensure the affinity and stability between this complex. In silico cloning was tested in an expression vector with positive results. In addition, the immune simulation for vaccine efficacy will be test. Through immunoinformatic approaches we constructed an effective multi-epitope vaccine candidate, that with further tests could contribute to prevention of pneumonia in a massive scale. Besides that, the study assists to better understanding of the immune mechanisms regarding M. pneumoniae infections and its interaction with the host.

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A NEW APPROACH TO RESEARCH THERAPEUTIC TARGETS FOR TRIPLE NEGATIVE BREAST CANCER: INVESTIGATION OF THE ASSOCIATION BETWEEN TUMOR GENOME AMPLIFIED REGIONS AND COMPETING ENDOGENOUS RNAS NETWORKS

A NEW APPROACH TO RESEARCH THERAPEUTIC TARGETS FOR TRIPLE NEGATIVE BREAST CANCER: INVESTIGATION OF THE ASSOCIATION BETWEEN TUMOR GENOME AMPLIFIED REGIONS AND COMPETING ENDOGENOUS RNAS NETWORKS

Igor S. Giner, Leandro E. Garcia, Bruna M. Sugita, Luciane R. Cavalli, Enilze Ribeiro, Jaqueline C. Oliveira and Daniela F. Gradia

Breast cancer (BC) is the second most common type of cancer in women in Brazil. By immunohistochemistry, BC is divided into four subtypes, among which the Triple Negative (TN) is the most aggressive. This subtype has no specific diagnosis or therapy. Thus, the research of therapeutic targets and biomarkers for TN BC is encouraged. It is known that competing endogenous RNAs (ceRNAs) networks are RNA-miRNA-RNA interaction networks that result in gene expression modification. Copy number alterations (CNAs) are gain or loss changes of chromosomal segments. We hypothesize that genome amplified regions in TN tumors may stimulate the formation of ceRNAs networks; this association’s investigation may be an alternative strategy for researching TN BC biomarkers and therapeutic targets. We aimed to identify potential ceRNAs transcribed in TN tumors genome amplified regions and explore this mechanism’s potential in the TN BC carcinogenesis regulation. A previous study realized by the research group identified CNAs in TN (n = 29) and Non-Triple Negative (n = 16) breast tumors using array-CGH. With this data, we performed a computational prediction of ceRNAs networks between transcripts from genome amplified regions in TN tumors and transcripts from the total transcriptome of Basal tumors (a molecular BC subtype, considered correspondent to TN in this study) – using the GDCRNATools package in the R software. We found a possible network of 8 pairs of overexpressed ceRNAs (logFC> 0.58, p-value ≤ 0.01, and positive correlation). Present in this network, TMPO-AS1 is a lncRNA with oncogenic functions already validated. The mir-302 and mir-520 miRNA families, described as tumor suppressors in the literature, are the most frequent in our network. The ceRNAs network around TMPO-AS1 and the most frequent miRNA families present themselves as potential candidates for specific TN BC therapy – showing that our analysis strategy can be an alternative to traditional research methodologies.