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Constant research on natural products has generated, over time, a large number of compounds with the potential to be evaluated in several biological tests and subsequently have been cataloged in databases that allow other researchers to perform virtual screenings of activity in various biological systems. This considerably reduces the time for the development of new drugs. This review describes the main databases of natural products available for searching bioactive compounds. It also describes the main features of virtual screening strategies for the identification of molecules with the potential to be used as new drugs. In addition, a search was made in the Web of Science database, using the search term "Virtual screening of natural products databases" from 2003 to 2018. The search criterion resulted in 230 articles, which had their abstracts evaluated with pertinence to the criteria required for this work, which are: a) be a research article; b) performing a virtual screening on databases of natural products or containing natural products; and c) works that identified drug candidate molecules. Based on these criteria, the bibliographic review on the topic was excluded. After this analysis, 104 works were selected for this review. We selected relevant papers describing the potential drug candidates that were distributed in 15 classes, of which the anticancer, antibacterial and anti-inflammatory hits were the most abundant. The works showing efforts to search for new molecules against various other diseases in distinct biological systems were also described. In this way, this work shows an overview of several methodologies and we hope they can help and inspire the development of new research to improve people's quality of life.

The first phytochemical study of the aerial parts of Maytenus erythroxylon Reissek resulted in the isolation of five triterpenes, two with a lupane skeleton: 29-norlupan-3,20-dione (1) and 30-hydroxy-20 (29) -lupen-3-one (2) and three with friedelane skeleton: 3,4-secofriedelan-3-oic acid (3), 3-oxo-30-hydroxyfriedelane (4) and 3β-Hydroxyfriedelane (5), where the compound (1) is reported for the first time in the Maytenus genus. The structures were identified through the analysis of uni and two-dimensional NMR spectral data. The isolated phases and compounds were subjected to in silico and in vitro techniques to evaluate the microbiological potential against microorganisms that cause intestinal disorders, showing that only the compound (3) was able to inhibit Candida spp. strains.

Background: Chemoinformatics has several applications in the field of drug design, helping to identify new compounds against a range of ailments. Among these are Leishmaniasis, effective treatments for which are currently limited. Objective: To construct new indole 2-aminothiophene molecules using computational tools and to test their effectiveness against Leishmania amazonensis (sp.). Methods: Based on the chemical structure of thiophene-indol hybrids, we built regression models and performed molecular docking, and used these data as bases for design of 92 new molecules with predicted pIC50 and molecular docking. Among these, six compounds were selected for the synthesis and to perform biological assays (leishmanicidal activity and cytotoxicity). Results: The prediction models and docking allowed inference of characteristics that could have positive influences on the leishmanicidal activity of the planned compounds. Six compounds were synthesized, one-third of which showed promising antileishmanial activities, with IC50 ranging from 2.16 and 2.97 μM (against promastigote forms) and 0.9 and 1.71 μM (against amastigote forms), with selectivity indexes (SI) of 52 and 75. Conclusion: These results demonstrate the ability of Quantitative Structure-Activity Relationship (QSAR)-based rational drug design to predict molecules with promising leishmanicidal potential, and confirming the potential of thiophene-indole hybrids as potential new leishmanial agents.

Background: Staphylococcus aureus is a gram-positive spherical bacterium commonly present in nasal fossae and in the skin of healthy people; however, in high quantities, it can lead to complications that compromise health. The pathologies involved include simple infections, such as folliculitis, acne, and delay in the process of wound healing, as well as serious infections in the CNS, meninges, lung, heart, and other areas. Aim: This research aims to propose a series of molecules derived from 2-naphthoic acid as a bioactive in the fight against S. aureus bacteria through in silico studies using molecular modeling tools. Methods: A virtual screening of analogues was done in consideration of the results that showed activity according to the prediction model performed in the KNIME Analytics Platform 3.6, violations of the Lipinski rule, absorption rate, cytotoxicity risks, energy of binder-receptor interaction through molecular docking, and the stability of the best profile ligands in the active site of the proteins used (PDB ID 4DXD and 4WVG). Results: Seven of the 48 analogues analyzed showed promising results for bactericidal action against S. aureus. Conclusion: It is possible to conclude that ten of the 48 compounds derived from 2-naphthoic acid presented activity based on the prediction model generated, of which seven presented no toxicity and up to one violation to the Lipinski rule.

Background: Neglected diseases require special attention when looking for new therapeutic alternatives, as these are diseases of extreme complexity and severity that affect populations belonging to lower social classes who are lacking access to basic rights such as basic sanitation. Introduction: Among the alternatives available for obtaining new drugs is Medicinal Chemistry, which is responsible for the discovery, identification, invention and preparation of prototypes. In this perspective, the present work aims to make a bibliographic review on the recent studies of Medicinal Chemistry applied to neglected diseases. Method: A literature review was carried out by searching the “Web of Sciences” database, including recent articles published in the Neglected Drug Design. Results: In general, it was noticed that the most studied neglected diseases corresponded to Chagas disease and leishmaniasis, with studies on organic synthesis, optimization of structures and molecular hybrids being the most used strategies. It is also worth mentioning the growing number of computationally developed studies, providing speed and optimization of costs in the procurement process. Conclusion: The CADD approach and organic synthesis studies, when applied in the area of Medicinal Chemistry proved to be important in the research and discovery of drugs for Neglected Diseases, since the planning of the experimental methodology used to obtain it, as well as in the selection of compounds with greater activity potential.

Aim: Selenium-based compounds have antitumor potential. We used a ligand-based virtual screening analysis to identify selenoglycolicamides with potential antitumor activity. Results & Conclusion: Compounds 3, 6, 7 and 8 were selected for in vitro cytotoxicity tests against various cell lines, according to spectrophotometry results. Compound 3 presented the best cytotoxicity results against a promyelocytic leukemia line (HL-60) and was able to induce cell death at a frequency similar to that observed for doxorubicin. The docking study showed that compound 3 has good interaction energies with the targets caspase-3, 7 and 8, which are components of the apoptotic pathway. These results suggested that selenium has significant pharmacological potential for the selective targeting of tumor cells, inducing molecular and cellular events that culminate in tumor cell death.

Pesticides are used to control and combat insects and pests in the agricultural sector, households, and public health programs. The frequent and disorderly use of these pesticides may lead to variety of undesired effects. Therefore, natural products have many advantages over to synthetic compounds to be used as insecticides. The goal of this study was to find natural products with insecticidal potential against Musca domestica and Mythimna separata. To achieve this goal, we developed predictive QSAR models using MuDRA, PLS, and RF approaches and performed virtual screening of 117 natural products. As a result of QSAR modeling, we formulated the recommendations regarding physico-chemical characteristics for promising compounds active against Musca domestica and Mythimna separata. Homology models were successfully built for both species and molecular docking of QSAR hits vs known insecticides allowed us to prioritize twenty-two compounds against Musca domestica and six against Mythimna separata. Our results suggest that pimarane diterpenes, abietanes diterpenes, dimeric diterpenes and scopadulane diterpenes obtained from aerial parts of species of the genus Calceolaria (Calceolariaceae: Scrophulariaceae) can be considered as potential insecticidal.

Infectious diseases are a health problem today and have high mortality rates with a wide diversity of potentially pathogenic microorganisms. Research that is based either on the search for new drugs from plants or on the improvement of phytotherapeutics is prominent and continues to play an important role nowadays. From this perspective, use of in silico studies to carry out investigations of new molecules potentially active for methicillin-resistant Staphylococcus aureus and Escherichia coli using an in-house database with 421 different secondary metabolites selected from the literature from Solanum genus was performed. We also realized an in vitro study with strains of S. aureus and E. coli and compared the results. Two databases from ChEMBL were selected, the first one with activity against methicillin-resistant S. aureus and another against E. coli. The compounds were classified according to the pIC50 values to generate and validate the model using a “Random Forest”. The “Random Forest” prediction model for methicillin-resistant S. aureus obtained an accuracy of 81%, area under the Receiver Operating Characteristic curve of 0.885, selecting eight molecules with an active potential above 60%. The prediction model for E. coli obtained an accuracy rate of 88%, area under the Receiver Operating Characteristic curve of 0.932, selecting four molecules with potential probability above 84%. Rutin proved to be potentially active in the in silico study for S. aureus and E. coli. Microbiological tests have shown that rutin has activity only for E. coli. An interaction study with strains of S. aureus ATCC 25923, a standard strain sensitive to all antibiotics, and SAM-01, a multidrug-resistant strain, was designed. There was interaction only between rutin and oxacillin, one of the three antibiotics studied in the interaction, for the strain SAM-01, reducing the resistance of this strain. Keywords: Rutin, Virtual Screening, Random Forest, Antibacterial activity

The objective of this work was to carry out a bibliographic survey of secondary metabolites isolated from the Velloziaceae family, creating a bank of compounds. After the bank was created, four prediction models for potentially active compounds against pathogenic microorganisms (Candida albicans, Escherichia coli, Pseudomonas aeruginosa and Salmonella sp.) were obtained trying to identify which metabolites would be more active against the strains. Four sets of compounds with known activity for microorganisms were selected for the construction of predictive models from the CHEMBL database. Another bank with 163 unique molecules isolated from the Velloziaceae family was built. The Volsurf+ v.1.0.7 software obtained the molecular descriptors and Knime 3.5 generated the in silico model. The performances of the internal and external tests were also analyzed. The study contributed through the virtual screening of a bank of metabolites to select several compounds with potential antimicrobial activity, highlighting the biflavonoid amentoflavone which showed potential activity against the four strains.

The present study investigated the activity of pyrimidine derivatives against Aedes aegypti. Two compounds, 3c and 3d showed excellent larvicide activity. Additionally, quantitative structure-activity relationship (QSAR) models were built using multiple-linear regression and partial least squares with descriptors generated from Dragon and VolSurf+ software, respectively. The best model is obtained with multiple linear regression (MLR), leading to a robust model. Moreover, the QSAR model is validated by means of some internal validation techniques in order to check its reliability, quality and robustness for predicting the larvicidal activity against A. aegypti. The models confirmed that the three-dimensional structure of molecules, steric properties, hydrophobic polar surface area, log partition (logP) and a simple pattern of substituent groups as methyl, methoxy, and succinimide in the pyrimidine derivatives are responsible for the larvicidal activity of the pyrimidine derivatives. Even more, the activity decreases by an electron-withdrawing group in R1 and increases when it is replaced by an aromatic ring activator group. These findings will aid in further studies of new pyrimidine derivatives active against Aedes aegypti.

Helicteres velutina K. Schum (Sterculiaceae), a member of Malvaceae sensu lato, is a Brazilian endemic plant that has been used by the indigenous tribe Pankarare as an insect repellent. A previous study has reported the isolation of terpenoids, flavonoids and pheophytins, in addition to the larvicidal activity of crude H. velutina extracts derived from the aerial components (leaves, branches/twigs, and flowers). The present study reports the biomonitoring of the effects of fractions and isolated compounds derived from H. velutina against A. aegypti fourth instar larvae. A crude ethanol extract was submitted to liquid&ndash, liquid extraction with hexane, dichloromethane, ethyl acetate and n-butanol to obtain their respective fractions. Larvicidal evaluations of the fractions were performed, and the hexane and dichloromethane fractions exhibited greater activities than the other fractions, with LC50 (50% lethal concentration) values of 3.88 and 5.80 mg/mL, respectively. The phytochemical study of these fractions resulted in the isolation and identification of 17 compounds. The molecules were subjected to a virtual screening protocol, and five molecules presented potential larvicidal activity after analyses of their applicability domains. When molecular docking was analysed, only three of these compounds showed an ability to bind with sterol carrier protein-2 (1PZ4), a protein found in the larval intestine. The compounds tiliroside and 7,4&prime, di-O-methyl-8-O-sulphate flavone showed in vitro larvicidal activity, with LC50 values of 0.275 mg/mL after 72 h and 0.182 mg/mL after 24 h of exposure, respectively. This is the first study to demonstrate the larvicidal activity of sulphated flavonoids against A. aegypti. Our results showed that the presence of the OSO3H group attached to C-8 of the flavonoid was crucial to the larvicidal activity. This research supports the traditional use of H. velutina as an alternative insecticide for the control of A. aegypti, which is a vector for severe arboviruses, such as dengue and chikungunya.

The microorganism Staphylococcus aureus is a gram-positive spherical bacteria present in the healthy human body, commonly found in the nostrils and skin. It is responsible for a number of infections such as inflammation in the follicles, contribution to the onset of acne, inflammation in the meninges, cardiovascular inflammation, lung inflammation and others. Benzoic compounds are widely used as drug prototypes for various diseases such as cancer, degenerative diseases, microbiological infections and inflammation, and viral infections. This work aims to propose new benzoic in silico bioactives to combat Staphylococcus aureus. To do this, a series of benzoic acid derivatives were submitted to a prediction model of biological activity developed in the KNIME Analytics Platform 3.6, where the molecules that showed activity in the model were imported into OSIRIS DataWarrior 4.7.3 to predict the risks of cytotoxicity, the calculation of the Lipinski rule violations and the absorption rate (% ABS). For the molecules approved by the virtual screening already commented, the calculation of the energies of interaction between receptor and binder by molecular docking and the analysis of the interactions with the residues of amino acids were carried out, comparing with the interactions of the drugs used as control in this research. As conclusion of this work it was possible to propose bioactive molecules against S. aureus based on the obtained computational data.

Background: Hepatitis C is a disease that constitutes a serious global health problem, is often asymptomatic and difficult to diagnose and about 60-80% of infected patients develop chronic diseases over time. As there is no vaccine against hepatitis C virus (HCV), developing new cheap treatments is a big challenge. Objective: The search for new drugs from natural products has been outstanding in recent years. The aim of this study was to combine structure-based and ligand-based virtual screening (VS) techniques to select potentially active molecules against four HCV target proteins from in-house secondary metabolite dataset (SistematX). Materials and Methods: From the ChEMBL database, we selected four sets of 1199, 355, 290 and 237chemical structures with inhibitory activity against different targets of HCV to create random forest models with an accuracy value higher than 82% for cross-validation and test sets. Afterward, a ligandbased virtual screen of the entire 1848 secondary metabolites database stored in SistematX was performed. In addition, a structure-based virtual screening was also performed for the same set of secondary metabolites using molecular docking. Results: Finally, using consensus analyses approach combining ligand-based and structure-based VS, three alkaloids were selected as potential anti-HCV compounds. Conclusion: The selected structures are a starting point for further studies in order to develop new anti- HCV compounds based on natural products.