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DRUG-GENE EXPRESSION PROFILES AND SYSTEMS BIOLOGY APPROACH TO IDENTIFY REPURPOSED DRUG CANDIDATES FOR TARGETING SCLEROSTIN IN PERI-IMPLANTITIS DISEASE.

DRUG-GENE EXPRESSION PROFILES AND SYSTEMS BIOLOGY APPROACH TO IDENTIFY REPURPOSED DRUG CANDIDATES FOR TARGETING SCLEROSTIN IN PERI-IMPLANTITIS DISEASE.

Dr.Pradeep Kumar Yadalam

Successful identification of a therapeutic strategy to treat patients with periimplantitis remains extremely important as post-implant bone degradation leads to implant failure and extreme bone loss. Given that the establishment of a new drug is quite expensive and time-consuming, the drug repurposing approach has come in handy. It helps to identify the experimental drugs that are beyond the purview of the initial clinical indication. In our current study, we propose a three-step drug repurposing approach in treating peri-implant bone defects and investigating the action of the FDA approved drugs to inhibit the key protein Sclerostin, involved in bone degradation. As the preliminary step, we differentiated the gene expression pattern in periimplantitis and dentate patients with their drug-induced profiles to identify the primary lead candidates. As the second step, we employed the computational biology approach to evaluate the protein-drug interaction and segregate the best hits among the identified lead compounds for sclerostin. Finally, the mode of action network for each candidate is established with the help of literature support, and the drug enrichment and pathway analysis are performed on the target genes in the network to evaluate the drug efficacy. This approach provided us with a drug interaction profile and specific genes and biomarkers to target bone mineralization in peri-implantitis. Thus, our three-step drug repurposing method is consistent with identifying the drug molecules with high efficacy and developing an efficient therapeutic strategy to treat peri-implantitis.

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VIRTUAL SCREENING OF SUBSTANCES WITH POTENTIAL ANTIVIRAL ACTIVITY AGAINST THREE FLAVIVIRUSES: dengue virus, yellow fever virus and Zika virus

VIRTUAL SCREENING OF SUBSTANCES WITH POTENTIAL ANTIVIRAL ACTIVITY AGAINST THREE FLAVIVIRUSES: dengue virus, yellow fever virus and Zika virus

Mateus Serafim, Thales Kronenberger, Rafael Rocha, Rafaela Ferreira, Vinícius Maltarollo, Bruno Mota and Erna Kroon

Approximately three billion people live in regions at risk of infections by flaviviruses. Dengue virus (DENV), Zika virus (ZIKV) and Yellow fever virus (YFV) presents outbreaks and severe complications. Currently, there are no antivirals available to treat these diseases. We screened and evaluated the potential antiviral activity of small molecules against these viruses, targeting the viral protease NS2B-NS3 (NS3PRO). We used a combination of HQSAR models and structural molecular modelling, based on structures of peptidomimetic DENV-3 NS3PRO inhibitors and molecular docking studies to screen for new compounds. Binding sites of DENV-3 and ZIKV NS3PRO were assessed to build a pharmacophoric model for virtual screening. Hits were selected after molecular dynamics simulations, with predictions of toxicity and biological activity. Biological activities were evaluated by the MTT assay. Antiviral activity was evaluated by plaque reduction, pre-treatment and virucide activity assays. Enzymatic inhibition assays against ZIKV NS3PRO were carried out. An optimal HQSAR model (q2 = 0.67; r2 = 0.87) was selected. A virtual screening of ~7,600,000 compounds was conducted (pharmacophore, docking and molecular dynamics), identifying eight potential inhibitors to the NS3PRO, with favorable biological activity (5/8) and toxicity (8/8) predictions. Five were active against ZIKV, YFV, DENV-2 or DENV-3 (EC50 from 4.21 ± 0.14 to 37.51 ± 0.8 µM, with selective indexes from 1.42 to 3.74), with one being active against all viruses. In plaque reduction assays, two substances reduced about 1.0 to 1.5 log10 of the viral titer of ZIKV, YFV and DENV-2. One also reduced about 1.0 log10 of YFV titer in pre-treatment assays. We have identified five compounds with antiviral activity, with one showing a potential panflavivirus activity. Preliminary ZIKV NS3PRO inhibition assays showed three active compounds with IC50 values between 28 and 69 µM.

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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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Virtual screening suggest potential affinity between Corynebacterium ulcerans essential proteins and inedited synthetic derivatives of tetraisoquinoline alkaloids

Virtual screening suggest potential affinity between Corynebacterium ulcerans essential proteins and inedited synthetic derivatives of tetraisoquinoline alkaloids

Luis Felipe de Morais Melo, Gustavo Andrew Mahon Mendes Pereira, Luis Cezar Rodrigues and Edson Luiz Folador

Corynebacterium ulcerans is aerobic, gram-positive bacteria that causes diphtheria, by infecting several hosts have a larger reservoir than the other causative agents. Considered reemergent, isolated cases due C. ulcerans diphtheria have increased even in immunized nations, highlighting the importance to seek new drugs and treatments. In previous work, we applied the interolog mapping method to generate the interactome, identifying the conserved hub proteins for 10 C. ulcerans strains, whose Database of Essential Genes (DEG) validation, COG classification and GO analysis, were confirmed the essentiality of 457 hub proteins, 351 having less than 30% identity against the host, being potential pharmacological targets. Here, we submitted the 351 non-host homologous hub proteins to Phyre2, resulting in 119 viable three-dimensional structure (more than 90% of the amino acids in Ramachandran plot favorable regions). Submitted to fpocket, 145 pockets with drugability score >= 0.5 were identified, which after being subjected to molecular docking in Autodock Vina against a library containing 42 inedited synthetic derivatives of tetraisoquinolinic alkaloid molecules resulted in 6,090 complex, 2,864 getting energy <= -6, considered relevant. The UvrABC system protein B, essential in the DNA repair process, formed the best complex with molecule23 reaching binding energy of -9.9, performing favorable interactions precisely with the protein residues binding to DNA, such as: hydrogen bonds (ARG379, LYS380 and SER166), Van der Waals interactions (ARG146, ASP376, ASP396, GLU122, GLU32, LYS134, MET372 and TYR116), pi-electron interactions (TYR119, TYR119 and TYR169), among others. Additionally, the molecule41 complexed with Bifunctional RNase H/acid phosphatase protein (-9.6); the molecule34 competes for the ADP binding site on Bifunctional protein (-9.5); the molecule20 competes for the uridina-difosfato-n-acetilglicosanima binding site on UDP-N-acetylglucosamine 1-carboxyvinyltransferase protein (-9.4). The results make it possible to understand the molecular binding mechanisms, enabling the rational optimization of molecules, reducing costs associated with synthesis and in-vitro or in-vivo tests.