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OPTIMIZATION OF SmTGR INHIBITORS USING A FRAGMENT-BASED DRUG DESIGN (FBDD) APPROACH

OPTIMIZATION OF SmTGR INHIBITORS USING A FRAGMENT-BASED DRUG DESIGN (FBDD) APPROACH

Rocío Riveros Maidana, Lauro Ribeiro de Souza Neto, Nicholas Furnham, Raymond J. Owens, José Brandão Neto, Frank von Delft, Ana Carolina Ramos Guimarães and Floriano Paes Silva Junior

Schistosomiasis is a neglected tropical disease caused by Schistosoma spp. Praziquantel (PZQ) is the unique drug used for the treatment of the disease. Despite the success of the treatment, the concern about the emergence of strains less sensitive to PZQ, and the possibility of evolution of drug resistance are growing. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite inside the human host. The Fragment-based Drug Design (FBDD) strategy consists of screening low molecular weight compounds against macromolecular targets (usually proteins) of clinical relevance. These small molecular fragments can bind at one or more sites on the target and act as starting points for the development of lead compounds. An FBDD screening campaign was performed obtaining 32 fragments that bind to 8 sites located at the SmTGR surface. From those sites, one secondary site was selected and fragments that bind to that site were optimized using a fragment-growing approach. The optimization was performed using the program AutoGrow 3.0. A total of 42 new ligands were generated from the initial fragments.

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DERIVATED OF DIBENZOYLMETHANE: IN SILICO ANALYSIS FOR DRUG DEVELOPMENT

DERIVATED OF DIBENZOYLMETHANE: IN SILICO ANALYSIS FOR DRUG DEVELOPMENT

Marcela Hauck, Mariá Braga, Jefferson Baêta, Amanda Gonçalves, Anésia Santos and Marisa Dia

In silico analysis is the beginning of many researches and it can predict which way follow it’s possible to evaluate the promisor compounds and the pathways of action. Most drugs for the treatment of cancer have limited efficacy and tumor recurrence rapidly follows. Therefore, the search for new molecules is necessary for the development of more effective clinical therapies. The family of beta-diketones, including dibenzoylmethane, is known by the large bioactivity, such as antitumor, antibacterial, and anti-inflammatory activities. Based on this, the aim of this study was evaluating in silico the derivate of dibenzoylmethane (ABB), one beta-diketone, as pharmacokinects, physicochemical and toxicity by ADMET and bioactivity score methods to a drug development. Using the web platforms Molinspiration Cheminformatics to draw the molecule and generate the SMILES code to run the bioactivity score and the preADMET and pkCSM to check the pharmacokinetics, physicochemical and toxicity, was possible to check all the parameters and use the Lipinski’s rule of five (Ro5) to validated the drug design. According to Ro5 the physicochemical parameters of this molecule was adequous to continue the drug-likeness. The evaluation of inhibitory effects of cytochrome p450 isoforms (CYP), known by monooxygenase family of enzymes, indicates that ABB isn’t an inhibitor of CYP1A2 and CYP2D6, but it inhibits the CYP2C1, CYP2C9 and CYP3A4. Those results show that ABB should be metabolized normally. In complement the test of mutagenicity of ABB showed negative for mutagenicity and carcinogenicity. The risk of hERG I inhibition was negative while for hERG II it was positive, indicating a low cardiotoxicity. In Molinspiration bioactivity score all the points checked were between -5 and 0 that shows a moderate bioactivity. These results showed that the ABB compound has great potencial to provide us with a potent drug in medical clinic and in vivo tests should be performed.