Chagas disease is an endemic disease caused by Trypanosoma cruzi, which affects more than eight million people, mostly in the Americas. A search for new treatments is necessary to control and eliminate this disease. Sesquiterpene lactones (SLs) are an interesting group of secondary metabolites characteristic of Asteraceae that have presented a wide range of biological activities. From the ChEMBL database, we selected a diverse set of 4,452, 1,635 and 1,322 structures with tested activity against the three T. cruzi parasitic forms, amastigote, trypomastigotes and epimastigote, respectively, to create random forest (RF) models with an accuracy of greater than 74 % for cross-validation and test sets. Afterwards, a ligand-based virtual screen of the entire SLs of Asteraceae database stored in SistematX (1,306 structures) was performed. In addition, a structure-based virtual screen was also performed for the same set of SLs using molecular docking. Finally, using an approach combining ligand-based and structure-based virtual screening along with the equations proposed in this study to normalize the probability scores, we verified potentially active compounds and established a possible mechanism of action.

Tuberculosis is one of the oldest known diseases of the world, remaining, within today, with the higher mortality rates caused by a single infectious agent, mainly represented by Mycobacterium tuberculosis. It's considered a greater public health problem, for reaching millions of people around the world, mainly in the developing countries, also highlighting their co-infection cases in immunocompromised patients, the example of HIV positive. Their high incidence rates are related to the non-adhesion to, and abandonment of, available treatment, due to its prolonged administration time, which allowed the appearance and increase of resistant strains causing tuberculosis. This evidences the need for the discovery and development of new drugs more efficient and powerful against pathogenic species of Mycobacterium genus. Classes of natural products, such as coumarins, have shown themselves to be powerful antimycobacteria agents in their evaluation against Mycobacterium strains. Thus, this work shows the synthesis, from protocols of O-Alkylation, O-Acetylation and Nitration well described in the literature, of coumarin derivatives, in good to greater yields, in most cases. This semi-synthetic derivatives, together with some commercial coumarins were evaluated according their antimycobacterial activities against M. tuberculosis H37Rv strains, where all demonstrated actives against the tested strains, inhibiting the growth of M. tuberculosis after eight weeks of observation, being more active than standard-drug used, Isoniazid, which non-inhibiting the growth of pathogens after the fourth week. Showing themselves as therapeutic alternatives in the development of new antimycobacterial active compounds.     

Molecular modeling by homology is a methodology widely used for the construction of protein structures that have not yet been crystallized. The constructed models can be used for the identification of inhibitors, representing a great method for the rational planning of drugs. Thus, the objective of the study was to construct the three-dimensional model of the protein structure of the enzyme Pteridine reductase 1 from Leishmania donovani (LdPTR1). PTR1 is an enzyme used in the metabolism of pterin from GTP, being considered an excellent specific target of drugs of Leishmania. The target protein and template sequences were obtained from the National Center for Biotechnology Information database and the 3D template structures through the Protein Data Bank (PDB). Sequence alignment was performed on the FASTA, yielding 91.0% identity and 97.2% similarity to the Leishmania major template protein (LmPtr1). The LdPtr1 model was constructed using MODELLER software 9.18. The stereochemical quality was evaluated in PROCHECK and the structural quality in VERIFY 3D and WHAT IF software. The Discovery Studio Visualizer software was used for graphical visualization of the modeled protein. Due to the high level of identity and similarity of the target enzymes and template, the results revealed that a good model was constructed. The Ramachandran graph showed that the conformations of the main chain of amino acids are in allowed and favored regions. Besides that; 85.07% of the residues have the protein sequence compatible with their 3D structure and do not have unusual atomic contacts.

The Asteraceae family belongs to the Asterales order, it consists of approximately 1,600 genera and 24,000 species, divided into 12 subfamilies and 44 tribes, is one of the largest families of angiosperms in the world, except Antarctica. Asteraceae is remarkable the presence of flavonoids, these have the necessary requirements to be used successfully in chemotaxonomy because are found in abundance in the Asteraceae, presents structural diversity, are stable structures and relatively easy to identify, therefore can be used as taxonomic markers. The aim of this study is to classify Asteraceae tribes based on the number of occurrences of flavonoids from our in-house databank (available at www.sistematx.ufpb.br) using descriptors calculated by DRAGON 7.0 software. The 2371 botanical occurrences with respective 74 molecular fragment descriptors were used as input data in SOM Toolbox 2.0 (Matlab) to generate Self-Organizing Maps (SOMs), classifying five tribes: tribes Anthemideae (A), Gnaphalieae (G), Tageteae (T), Senecioneae (S) and Carduoideae (CR).  The descriptor with positive contribution to the region where the flavonoids isolated from the tribes are located are: RFD that represents the ring fusion density; nArOH that represents the number of aromatic hydroxyls; nCIC descriptors which represent the number of rings in one molecule; NNRS representing the standard number of ring systems; nR05 which represents the number of 5-membered rings; nCbH representing the number of C (sp²) benzene unsubstituted; nHBonds which represents the number of intramolecular H bonds (O) and C-019 represents = CRX (= represents a double bond, R represents H and CH₃, X represents oxygen atom).

Predict Nanoparticles (NP) toxicity is one of the biggest deal for both toxicologists and computational chemistries. The Nanodesk project is a SUDOE interreg project (Project Code: SOE1/P1/E0215) aimed at the development of an interactive and easy to use web-platform which will be help the plastic industry in the selection of the safer nanomaterials (NMs). The web-platform will implement a series of machine learning approaches which will be identify the safer NMs amongst a list selected by the industry and the scientific committee of the project. The project has started on July 2016 and will last for 36 month.

Breast cancer is one of the different types of cancer that most affect women around the world. Clinically breast cancer is characterized as the presence or absence of hormone receptors and as to the hyper-expression (or not) of the protein HER2 (Epidermal Growth Factor Receptor Human Type 2). As signal transduction pathways are upregulated in many tumor cells, protein kinase inhibitors targeting these regulated pathways are attractive candidates for the search for new cancer therapies. An important class of compounds that has been outstanding for the planning and development of new drugs are the acridine derivatives, where more and more studies show that this class has promising activities for the therapeutic innovation of different diseases. In this study spiro-acridine derivatives (AMTAC-01 and AMTAC-02) that have potential activity antitumoral on the MCF-7 (breast adenocarcinoma) line with a GI50 (concentration of the compound that inhibits 50% cell growth) of 2.09 and 0.69 μm respectively were subjected to energy minimization and Molecular Docking calculations in HER2 and EGFR with the software Molegro Virtual Docker. The results showed that spiro-acridine derivatives fit well into the active site of the EGFR and HER2 and also interact with the active site residues that appear to be important for their biological activity. Therefore, spiro-acridine derivatives may be a dual inhibitor of EGFR/HER2 and may be used as potential candidates for anticancer drugs, specifically as HER2-positive breast cancer agents.

Background and aim: The global situation of bacterial diseases has become a concern in the last years due to the lack of new drugs and the antibiotic resistance. Since the year 2000, only eight antibacterial molecules have obtained a marketing authorization. Furthermore, despite the discovery over the last twenty years of compounds with an interesting antibiotic activity, few of them belong to new chemical classes or have the required properties to become drugs or to circumvent resistance problems.

At present, in order to accelerate the development of drugs with relatively low costs and reduced risks, pharmaceutical companies develop new approaches from existing drugs. This methodology known as drug repurposing allows the development of new indications for existing drugs with well-known pharmacokinetic profiles. We have previously described the antimicrobial activity of bisacodyl, drug used in therapeutics as laxative.

The aim of this study was to synthesize a new serie of triarylmethane (TAM) analogues of bisacodyl and study the antibacterial activity.

Figure 1: Pharmacomodulation of bisacodyl a) Symmetrical TAM, b) unsymmetrical TAM

Methods: The analogues of bisacodyl were synthesized from commercially available reagents via a Friedel-Crafts reaction followed by an O-alkylation then functionalization with PEG fragments to increase solubility. The bioassay was performed using polystyrene micro-assay plates (96 well) using levofloxacine, a broad-spectrum antibiotic, as a control.

Results: The antibacterial activity against Gram-positive and Gram-negative pathogens of the compound 4, 4’-(pyridin-2-ylmethylene) diphenol was evaluated. This compound exhibited antilisterial activity, with minimum inhibitory concentration (MIC) ranging from 6.25 to 12.5 µg/mL against Salmonella typhimurium. Additionally, it was active against Escherichia coli, Listeria monocytogene and Staphylococcus aureus with MIC values between 25-50 μg/mL and 12.5-25 μg/mL. The derivatives bearing PEG groups have also been tested revealing a promising antibacterial activity.

Conclusion: The studied compounds displayed a higher bacteriostatic activity compared to bisacodyl.

The increase in the volume of agroindustrial, agricultural and domestic solid wastes entails a series of implications related to health and environmental aspects. The objective of this research was to determine the chemical composition of agroindustrial residues of shelled peanuts, peanuts in shell, banana peels, cassava peels, shelled beans and beans peas for use in pigs. In the agroindustrial residues the content of matter (DM), organic matter (OM), crude protein (PB), crude fiber (FB), ashes, ethereal extract (EE), nitrogen free extracts, ELN and EB, Descriptive statistics were used and mean and standard deviation were determined. Peanut and shelled peanut residues showed the highest MS (91.65, 92.65%), PB (28.22, 28.27%), EE (40.49, 43.19%), and EB (577.68, 591.98 kcal kg MS^-1). Shelled beans had an acceptable ELN content (62.66%). In relation to the FB, the bean peel had the highest content (49.03 %). The banana peel and cassava presented the highest ash content (8.82 and 8.49 %) respectively. The agroindustrial by-products of shelled peanuts, peanuts, banana peels, cassava peels, peas and shelled beans presented good MS, MO, PB, ELN, EE, Ash and EB contents, all suitable for use in the pigs feedwell.

The reliability of physics-based in-silico studies of protein-ligand complexes highly depends on the quality of available structures and force-field parameters. Both these subjects have been largely addressed by both experimental and computational scientists from industry and academia. Yet, tasks like obtaining an initial structure with the correct protonation states and hydrogen-bond network or accurate force-field parameters for a given ligand can still be out of reach for the non-experts in those particular fields. Here we showcase two software tools that aim at bridging this gap: proteinPrepare [1,2] and parameterize. We show how these softwares can be easily used by the community and how we are integrating these tools within a wider computational pipeline for drug discovery.

1. Stefan Doerr, Toni Giorgino, Gerard Martínez-Rosell, João M. Damas, and Gianni De Fabritiis. High-Throughput Automated Preparation and Simulation of Membrane Proteins with HTMD. Journal of Chemical Theory and Computation 2017 13 (9), 4003-4011. DOI: 10.1021/acs.jctc.7b00480
2. Gerard Martínez-Rosell, Toni Giorgino, and Gianni De Fabritiis. PlayMolecule ProteinPrepare: A Web Application for Protein Preparation for Molecular Dynamics Simulations. Journal of Chemical Information and Modeling 2017 57 (7), 1511-1516. DOI: 10.1021/acs.jcim.7b00190

Computational methods have been widely used to characterize the catalytic mechanisms of several chemical systems namely enzymes. However, enzymes are studied using big chemical systems containing several thousands of atoms generating huge amounts of data that are hard to manipulate and analyze efficiently. Therefore, we developed molUP that is a user-friendly plugin for VMD to handle QM and ONIOM calculations performed using Gaussian software.

MolUP allows loading output files from Gaussian calculations and performs analysis concerning the structure of the chemical system as well as their energies and vibrational frequencies. Furthermore, molUP provides a graphical interface to manipulate the length of atomic bonds and the amplitude of angles and dihedral angles. Users can also easily choose which atoms belong to each ONIOM layer and the atoms that are free to move during a geometry optimization. At the end, molUP is capable of saving the new structure as a new Gaussian input file, ready to run a new calculation. Since molUP is a VMD extension, users can also benefit from the many features and resources available on VMD.

In order to demonstrate the potential of MolUP, we will also present the results that have been carried out in our research group regarding the catalytic mechanism of Serine HydroxyMethylTransferase (SHMT), using a QM/MM approach. SHMT is a pyridoxal-5'-phosphate (PLP)-dependent enzyme [1-3] that catalyzes the α-elimination of L-serine, where a methyl group is transferred from the substrate to a second cofactor, tetrahydrofolate (THF). The reaction occurs in six sequential steps from which the first one is the rate-limiting step with an activation barrier of 18.3 kcal/mol that closely fits the experimental k_cat of 0.98±0.06 s^-1 [4] (∆G^‡ ≈ 18.2 kcal/mol). This first step involves the nucleophilic attack of nitrogen from THF to the β-carbon of the substrate, promoting the α-elimination of the CH₂OH group of the substrate. The subsequent steps involve an intramolecular cyclization within the THF cofactor where the elimination product of the first step is incorporated, generating the 5,10-methyl-THF. At the end, the quinonoid intermediate (substrate + PLP) is protonated, producing glycine.

References:

[1] Oliveira, Eduardo F.; Cerqueira, Nuno M. F. S. A.; Fernandes, Pedro A. and Ramos, M.J., Journal of the American Chemical Society 2011, 133, 15496-15505

[2] Cerqueira, N. M. F. S. A.; Fernandes, P. A.; Ramos, M. J., Journal of Chemical Theory and Computation 2011, 7, 1356-1368

[3] Fernandes, H. S.; Ramos, M. J.; Cerqueira, N. M. F. S. A., Chem. Eur. J. 2017, 23, 9162.

[4] Sopitthummakhun K.; Maenpuen S.; Yuthavong Y.; Leartsakulpanich U.; Chaiyen P., Febs Journal 2009, 276 (15), 4023-4036.