The demand for new therapies has encouraged the development of faster and cheaper methods of drug design. Considering the number of potential biological targets for new drugs, the docking-based virtual screening (DBVS) approach has occupied a prominent role among modern strategies for identifying new bioactive substances. Some tools have been developed to validate docking methodologies and identify false positives, such as the receiver operating characteristic (ROC) curve. In this context, a database with 31 molecular targets called the Our Own Molecular Targets Data Bank (OOMT) was validated using the root-mean-square deviation (RMSD) and the area under the ROC curve (AUC) with two different docking methodologies: AutoDock Vina and DOCK 6. Sixteen molecular targets showed AUC values of >0.8, and those targets were selected for molecular docking studies. The drug-likeness properties were then determined for 473 Brazilian natural compounds that were obtained from the ZINC database. Ninety-six compounds showed similar drug-likeness property values to the marked drugs (positive values). These compounds were submitted to DBVS for 16 molecular targets. Our results showed that AutoDock Vina was more appropriate than DOCK 6 for performing DBVS experiments. Furthermore, this work suggests that three compounds-ZINC13513540, ZINC06041137, and ZINC1342926-are inhibitors of the three molecular targets 1AGW, 2ZOQ, and 3EYG, respectively, which are associated with cancer. Finally, since ZINC and the PDB were solely created to store biomolecule structures, their utilization requires the application of filters to improve the first steps of the drug development process. Graphical Abstract Evaluation of docking methods used for virtual screening.

RESUMO Os bancos de dados são uma ferramenta importante de gerenciamento de informações. A organização de alvos moleculares em um banco específico possibilita a rápida triagem de compostos protótipos e agiliza os ensaios biológicos, diminuindo os custos e o tempo de pesquisa de novos compostos(PDB). O PDB organiza um banco de dados de estruturas de macromoléculas biológicas, sendo atualmente uma ferramenta muito utilizada por diversos grupos de pesquisadores. Atualmente o PDB conta com diversos implementos para facilitar o uso e análise dos dados estruturais disponíveis, tornando-se um recurso extraordinário para a pesquisa biológica.De forma similar, a Triagem Virtual Inversa 2 (TVI) é uma ferramenta que permite a rápida identificação de novos alvos moleculares. Através da TVI é possível fazer a predição da atividade, bem como da seletividade de um composto e com isso obter um grupo de compostos para serem testados em ensaios biológicos. No entanto, embora as metodologias de TVI sejam 1 e-mail: anapaulacarregal@gmail.com Universidade Federal de São João del capazes de encontrar alvos moleculares específicos, nem sempre os ensaios biológicos estão disponíveis para as pesquisas brasileiras, dificultando os projetos de desenvolvimento de fármacos. Assim, o objetivo deste trabalho é a criação do nosso próprio banco de alvos moleculares, denominado de our own molecular targets data bank (OOMT), que será continuamente aperfeiçoado a fim de realizar ensaios de TVI e, posteriormente ensaios biológicos num curto período de tempo, integrando químicos sintéticos, medicinais e biólogos moleculares. O diferencial encontra-se na disponibilidade de realização dos ensaios biológicos no próprio campus. MATERIAL E MÉTODOSTodas as proteínas incluídas no OOMT são objetos de pesquisas experimentais na Universidade Federal de São João del-Rei (UFSJ/CCO). As estruturas cristalográficas foram obtidas do PDB. Para quantificar a similaridade entre o complexo cristalográfico obtido do PDB e o complexo obtido pela ancoragem molecular usando o Autodock Vina 3 , foi realizado um cálculo de desvio médio quadrático (root mean square deviation -RMSD,), através do software Discovery Studio Visualizer 2.5 4 . Aqueles complexos que apresentaram um RMSD menor ou igual a dois, foram incluídos no banco de dados, aqueles cujo valor excedia dois foram descartados. RESULTADOS E DISCUSSÃOA partir dos valores de RMSD foram incluídos 34 alvos no OOMT. A Figura 1 mostra a sobreposição dos ligantes cristalográficos das proteínas com código PDB 3BZ3 em A e 2VV9 em B. Essas proteínas apresentaram valores de RMSD de 0,325 e 0,520, respectivamente. Esses valores indicam que o programa Autodock Vina é capaz de reproduzir de maneira similar as interações intermoleculares dos complexos depositados no PDB.

Several medicinal plants have been studied in recent years in Brazil. However, despite many efforts, the pharmacological mechanisms of many natural products are still unknown. Several biological assays in vivo and in vitro are needed to further address this issue, which increases the cost of these studies. The main goal of this study was to apply the methodology of inverse virtual screening (IVS), followed by docking studies, and refinement by molecular dynamics (MD) simulation and quantum mechanical/molecular mechanical to determine the pharmacological receptors for five selected natural products with the exception of the benzoxazinone isolated from the exudate of the radicle of the crop species which were mainly isolated from the Cerrado species, obtained from Cerrado, a typical Brazilian biome. Initially, the structures of the natural compounds were generated using the online software program sc-PDB, which searches for molecular targets deposited in the protein data bank. The ligands were docked against target proteins found in IVS stepforming complexes, which were refined again using MD simulations by ff03 force field for 1 ns. Finally, the binding energy for each complex was obtained by the ONIOM (PM6:UFF) method. As a result, these calculations suggested possible molecular targets for these natural compounds. Among the targets found were 1EH4, 2A4Z, 1H49, 1JT2, 2BNJ, and 3FW9, which are involved in cancer and rheumatoid arthritis pathologies, indicating that they are promising molecular targets. In this study, we proposed a biological assay for these natural compounds. The results indicate that structural changes may be proposed to generate compounds that are able to bind more strongly to the receptor and become new drug candidates, thus optimizing the search for lead natural compounds.

n e u r o t r a n s m i s s o r e s d a a d r e n a l i n a , s e r o t o n i n a e a d e n o s i n a f o r a m s u b m e t i d o s a o p r o g r a m a o n -l i n e s c -P D B . O n z e v a r i á v e i s f o r a m e s t u d a d a s , c a d a u m a s e p a r a d a m e n t e , m a n t e n d o a s d e m a i s s e g u n d o o d e f a u l t d o p r o g r a m a . A p ó s e s s e

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