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Over the years the study of the quantitative structure-activity relationship (QSAR) has transformed from a simple regression analysis to the implementation of machine learning (ML) with multiple statistics. Today ML-based QSAR models are quite important and play a notable role in drug design and screening, property prediction, biological activity, etc. ML methods applied to QSAR build classification or regression models to describe/predict the complex relationships between the chemical structure of molecules and biological activity. Even with the increase in scientific publications addressing this topic written in Portuguese, there is still a shortage of scientific articles explaining ML techniques applied to QSAR, how to build models, the types of models, algorithms, for the Brazilian scientific community. And to fill this need, we intend to approach the subject in a simple and didactic way for students and researchers who are starting in this very promising and important area. We will describe the fully explained theory of machine learning by applying QSAR, abstracting the complexity, and well-illustrated.

Background: Alzheimer’s disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer’s disease. Co-targeting GSK3β and BChE in Alzheimer’s disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer’s disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Results: Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of −9.6 and −12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. Conclusion: In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer’s disease, capable of simultaneously inhibiting both GSK-3β and BuChE.

In 2019, the emergence of the seventh known coronavirus to cause severe illness in humans triggered a global effort towards the development of new drugs and vaccines for the SARS-CoV-2 virus. These efforts are still ongoing in 2024, including the present work where we conducted a ligand-based virtual screening of terpenes with potential anti-SARS-CoV-2 activity. We constructed a Quantitative Structure–Activity Relationship (QSAR) model from compounds with known activity against SARS-CoV-2 with a model accuracy of 0.71. We utilized this model to predict the activity of a series of 217 terpenes isolated from the Fabaceae family. Four compounds, predominantly triterpenoids from the lupane series, were subjected to an in vitro phenotypic screening in Vero CCL-81 cells to assess their inhibitory activity against SARS-CoV-2. The compounds which showed high rates of SARS-CoV-2 inhibition along with substantial cell viability underwent molecular docking at the SARS-CoV-2 main protease, papain-like protease, spike protein and RNA-dependent RNA polymerase. Overall, virtual screening through our QSAR model successfully identified compounds with the highest probability of activity, as validated using the in vitro study. This confirms the potential of the identified triterpenoids as promising candidates for anti-SARS-CoV-2 therapeutics.

Candida species are frequently implicated in the development of both superficial and invasive fungal infections, which can impact vital organs. In the quest for novel strategies to combat fungal infections, there has been growing interest in exploring synthetic and semi-synthetic products, particularly chromone derivatives, renowned for their antimicrobial properties. In the analysis of the antifungal activity of the compound (E)-benzylidene-chroman-4-one against Candida, in silico and laboratory tests were performed to predict possible mechanisms of action pathways, and in vitro tests were performed to determine antifungal activity (MIC and MFC), to verify potential modes of action on the fungal cell membrane and wall, and to assess cytotoxicity in human keratinocytes. The tested compound exhibited predicted affinity for all fungal targets, with the highest predicted affinity observed for thymidylate synthase (−102.589 kJ/mol). MIC and CFM values ranged from 264.52 μM (62.5 μg/mL) to 4232.44 μM (1000 μg/mL). The antifungal effect likely occurs due to the action of the compound on the plasma membrane. Therefore, (E)-benzylidene-chroman-4-one showed fungicidal-like activity against Candida spp., possibly targeting the plasma membrane.

The critical enzyme dihydrofolate reductase-thymidylate synthase in Leishmania major (LmDHFR-TS) serves a dual-purpose role and is essential for DNA synthesis, a cornerstone of the parasite’s reproductive processes. Consequently, the development of inhibitors against LmDHFR-TS is crucial for the creation of novel anti-Leishmania chemotherapies. In this study, we employed an in-house database containing 314 secondary metabolites derived from cinnamic acid that occurred in the Asteraceae family. We conducted a combined ligand/structure-based virtual screening to identify potential inhibitors against LmDHFR-TS. Through consensus analysis of both approaches, we identified three compounds, i.e., lithospermic acid (237), diarctigenin (306), and isolappaol A (308), that exhibited a high probability of being inhibitors according to both approaches and were consequently classified as promising hits. Subsequently, we expanded the binding mode examination of these compounds within the active site of the test enzyme through molecular dynamics simulations, revealing a high degree of structural stability and minimal fluctuations in its tertiary structure. The in silico predictions were then validated through in vitro assays to examine the inhibitory capacity of the top-ranked naturally occurring compounds against LmDHFR-TS recombinant protein. The test compounds effectively inhibited the enzyme with IC50 values ranging from 6.1 to 10.1 μM. In contrast, other common cinnamic acid derivatives (i.e., flavonoid glycosides) from the Asteraceae family, such as hesperidin, isovitexin 4′-O-glucoside, and rutin, exhibited low activity against this target. The selective index (SI) for all tested compounds was determined using HsDHFR with moderate inhibitory effect. Among these hits, lignans 306 and 308 demonstrated the highest selectivity, displaying superior SI values compared to methotrexate, the reference inhibitor of DHFR-TS. Therefore, continued research into the anti-leishmanial potential of these C6C3-hybrid butyrolactone lignans may offer a brighter outlook for combating this neglected tropical disease.

The characterization and cytotoxicity of the essential oil from Conyza bonariensis (L.) aerial parts (CBEO) were previously conducted. The major compound was (Z)-2-lachnophyllum ester (EZ), and CBEO exhibited significant ROS-dependent cytotoxicity in the melanoma cell line SK-MEL-28. Herein, we employed the Molegro Virtual Docker v.6.0.1 software to investigate the interactions between the EZ and Mitogen-Activated Protein Kinases (MAPKs), the Nuclear Factor kappa B (NF-κB), and the Protein Kinase B (PKB/AKT). Additionally, in vitro assays were performed in SK-MEL-28 cells to assess the effect of CBEO on the cell cycle, apoptosis, and these signaling pathways by flow cytometry and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using MAPKs inhibitors. CBEO induced a significant increase in the sub-G1 peak, as well as biochemical and morphological changes characteristic of apoptosis. The in-silico results indicated that EZ interacts with Extracellular Signal-Regulated Kinase 1 (ERK1), c-Jun N-terminal Kinase 1 (JNK1), p38α MAPK, NF-κB, and PKB/AKT. Moreover, CBEO modulated the ERK1/2, JNK, p38 MAPK, NF-κB, and PKB/AKT activities in SK-MEL-28 cells. Furthermore, CBEO’s cytotoxicity against SK-MEL-28 cells was significantly altered in the presence of MAPKs inhibitors. These findings support the in vitro antimelanoma effect of CBEO through apoptosis induction, and the modulation of ERK, JNK, p38 MAPK, NF-κB, and PKB/AKT activities.

Major depressive disorder is a severe mood disorder characterized by different emotions and feelings. This study investigated the antidepressant activity of the phenylpropanoid methyleugenol (ME) in adult female mice exposed to a stress model induced by dexamethasone. The animals were randomly divided into groups containing eight animals and were pre-administered with dexamethasone (64 μg/kg subcutaneously). After 165 and 180 min, they were treated with ME (25, 50 and 100 mg/kg intraperitoneally) or imipramine (10 mg/kg intraperitoneally) after 45 min and 30 min, respectively; they were then submitted to tests which were filmed. The videos were analyzed blindly. In the tail suspension test, ME (50 mg/kg) increased latency and reduced immobility time. In the splash test, ME (50 mg/kg) decreased grooming latency and increased grooming time. In the open field, there was no statistical difference for the ME groups regarding the number of crosses, and ME (50 mg/kg) increased the number of rearing and time spent in the center. Regarding in silico studies, ME interacted with dopaminergic D1 and α1 adrenergic pathway receptors and with tryptophan hydroxylase inhibitor. In the in vivo evaluation of the pathways of action, the antidepressant potential of ME (50 mg/kg) was reversed by SCH23390 (4 mg/kg intraperitoneally) dopaminergic D1 receptor, Prazosin (1 mg/kg intraperitoneally) α1 adrenergic receptor, and PCPA (4 mg/kg intraperitoneally) tryptophan hydroxylase inhibitor. Our findings indicate that ME did not alter with the locomotor activity of the animals and shows antidepressant activity in female mice with the participation of the D1, α1 and serotonergic systems.

Cancer is a multifactorial disease that continues to increase. Lignans are known to be important anticancer agents. However, due to the structural diversity of lignans, it is difficult to associate anticancer activity with a particular subclass. Therefore, the present study sought to evaluate the association of lignan subclasses with antitumor activity, considering the genetic profile of the variants of the selected targets. To do so, predictive models were built against the targets tyrosine-protein kinase ABL (ABL), epidermal growth factor receptor erbB1 (EGFR), histone deacetylase (HDAC), serine/threonine-protein kinase mTOR (mTOR) and poly [ADP-ribose] polymerase-1 (PARP1). Then, single nucleotide polymorphisms were mapped, target mutations were designed, and molecular docking was performed with the lignans with the best predicted biological activity. The results showed more anticancer activity in the dibenzocyclooctadiene, furofuran and aryltetralin subclasses. The lignans with the best predictive values of biological activity showed varying binding energy results in the presence of certain genetic variants.

Schistosomiasis is a chronic parasitic disease caused by trematodes of the genus Schistosoma; it is commonly caused by Schistosoma mansoni, which is transmitted by Bioamphalaria snails. Studies show that more than 200 million people are infected and that more than 90% of them live in Africa. Treatment with praziquantel has the best cost–benefit result on the market. However, hypersensitivity, allergy, and drug resistance are frequently presented after administration. From this perspective, ligand-based and structure-based virtual screening (VS) techniques were combined to select potentially active alkaloids against S. mansoni from an internal dataset (SistematX). A set of molecules with known activity against S. mansoni was selected from the ChEMBL database to create two different models with accuracy greater than 84%, enabling ligand-based VS of the alkaloid bank. Subsequently, structure-based VS was performed through molecular docking using four targets of the parasite. Finally, five consensus hits (i.e., five alkaloids with schistosomicidal potential), were selected. In addition, in silico evaluations of the metabolism, toxicity, and drug-like profile of these five selected alkaloids were carried out. Two of them, namely, 11,12-methylethylenedioxypropoxy and methyl-3-oxo-12-methoxy-n(1)-decarbomethoxy-14,15-didehydrochanofruticosinate, had plausible toxicity, metabolomics, and toxicity profiles. These two alkaloids could serve as starting points for the development of new schistosomicidal compounds based on natural products.

Abstract This study evaluated the orofacial antinociceptive effect of (S)-(-)-perillyl alcohol (PA) associated with codeine (C) and investigated the possible molecular anchorage mechanisms of PA. Mice (n = 5 per group) were treated with PA alone and associated with codeine and assigned to the following groups: 75.0 mg/kg PA; 75.0 mg/kg PA + C 30 mg/kg; PA 37.5 mg/kg + C 15.0 mg/kg; C 30.0 mg/kg; and control. Nociception was induced by formalin, capsaicin, and glutamate, and was quantified based on the duration (in seconds) of face grooming. The possible mechanisms of action were evaluated by molecular docking study. In the formalin test, PA75/C30 presented an effect in the neurogenic (p < 0.0001) and inflammatory (p < 0.005) phases. Mice treated with PA75 (p < 0.0001) and PA75/C30 (p < 0.0005) showed a reduced nociceptive behavior in the capsaicin test. Glutamate-induced nociception also was blocked by PA75 (p < 0.0005) and C30 (p < 0.0005). The molecular anchorage analysis indicated high negative binding energy values for the evaluated receptors, especially glutamate receptors (AMPA -79.57 Kcal/mol, mGLUR6 -71.25, and NMDA -66.33 Kcal/mol). PA associated with codeine showed orofacial antinociceptive activity, with theoretical evidence of interaction with glutamate receptors.

Chalcones are direct precursors in the biosynthesis of flavonoids. They have an α,β-unsaturated carbonyl system which gives them broad biological properties. Among the biological properties exerted by chalcones, their ability to suppress tumors stands out, in addition to their low toxicity. In this perspective, the present work explores the role of natural and synthetic chalcones and their anticancer activity in vitro reported in the last four years from 2019 to 2023. Moreover, we carried out a partial least square (PLS) analysis of the biologic data reported for colon adenocarcinoma lineage HCT-116. Information was obtained from the Web of Science database. Our in silico analysis identified that the presence of polar radicals such as hydroxyl and methoxyl contributed to the anticancer activity of chalcones derivatives. We hope that the data presented in this work will help researchers to develop effective drugs to inhibit colon adenocarcinoma in future works.

The use of agrochemicals has become a standard practice worldwide to ensure the productivity and quality of sugarcane crops. This study aimed to analyze the metabolic changes in sugarcane culms treated with five different nematicides. The experimental design was randomized in blocks, and agro-industrial and biometric variables were evaluated. The samples were extracted and then analyzed using LC–MS, LC–MS/MS, and LC–HRMS. The data obtained were submitted to statistical methods (PCA and PLS). Fragmentation patterns, retention time, and UV absorptions of the main features were analyzed. The plantations treated with carbosulfan (T4) obtained higher agricultural productivity and total recoverable sugar (TRS), while the use of benfuracarb (T3) was associated with lower growth and lower TRS. Statistical analysis revealed the contribution of the features at m/z 353 and m/z 515, assigned as chlorogenic acids, which discriminated the groups. The MS profile also supported the occurrence of flavonoids (C-glycosides and O-glycosides) in the samples.

The bifunctional enzyme Dihydrofolate reductase-thymidylate synthase (DHFR-TS) plays a crucial role in the survival of the Leishmania parasite, as folates are essential cofactors for purine and pyrimidine nucleotide biosynthesis. However, DHFR inhibitors are largely ineffective in controlling trypanosomatid infections, largely due to the presence of Pteridine reductase 1 (PTR1). Therefore, the search for structures with dual inhibitory activity against PTR1/DHFR-TS is crucial in the development of new anti-Leishmania chemotherapies. In this research, using the Leishmania major DHFR-TS recombinant protein, enzymatic inhibitory assays were performed on four kauranes and two derivatives that had been previously tested against LmPTR1. The structure 302 (6.3 µM) and its derivative 302a (4.5 µM) showed the lowest IC50 values among the evaluated molecules. To evaluate the mechanism of action of these structures, molecular docking calculations and molecular dynamics simulations were performed using a DHFR-TS hybrid model. Results showed that hydrogen bond interactions are critical for the inhibitory activity against LmDHFR-TS, as well as the presence of the p-hydroxyl group of the phenylpropanoid moiety of 302a. Finally, additional computational studies were performed on DHFR-TS structures from Leishmania species that cause cutaneous and mucocutaneous leishmaniasis in the New World (L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes in these species. It was demonstrated that structures 302 and 302a are multi-Leishmania species compounds with dual DHFR-TS/PTR1 inhibitory activity.

Natural products have important pharmacological activities. This study sought to investigate the activity of the compound betulinic acid (BA) against different strains of bacteria and fungi. The minimum inhibitory concentration (MIC) was determined and then the minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC). After performing the in vitro tests, molecular modeling studies were carried out to investigate the mechanism of action of BA against the selected microorganisms. The results showed that BA inhibited the growth of microbial species. Among the 12 species (Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa, Escherichia coli, Mycobacterium tuberculosis, Candida albicans, C. tropicalis, C. glabrata, Aspergillus flavus, Penicillium citrinum, Trichophyton rubrum, and Microsporum canis) investigated, 9 (75%) inhibited growth at a concentration of 561 µM and 1 at a concentration of 100 µM. In general, the MBC and MFC of the products were between 561 and 1122 μM. In silico studies showed that BA presented a mechanism of action against DNA gyrase and beta-lactamase targets for most of the bacteria investigated, while for fungi the mechanism of action was against sterol 14α-demethylase (CYP51) targets and dihydrofolate reductase (DHFR). We suggest that BA has antimicrobial activity against several species.

Candida albicans is associated with serious infections in immunocompromised patients. Terpenes are natural-product derivatives, widely studied as antifungal alternatives. In a previous study reported by our group, the antifungal activity of α-pinene against C. albicans was verified; α-pinene presented an MIC between 128–512 µg/mL. In this study, we evaluate time-kill, a mechanism of action using in silico and in vitro tests, anti-biofilm activity against the Candida albicans, and toxicity against human cells (HaCaT). Results from the molecular-docking simulation demonstrated that thymidylate synthase (−52 kcal mol−1), and δ-14-sterol reductase (−44 kcal mol−1) presented the best interactions. Our in vitro results suggest that α-pinene’s antifungal activity involves binding to ergosterol in the cellular membrane. In the time-kill assay, the antifungal activity was not time-dependent, and also inhibited biofilm formation, while rupturing up to 88% of existing biofilm. It was non-cytotoxic to human keratinocytes. Our study supports α-pinene as a candidate to treat fungal infections caused by C. albicans.

Sesquiterpene lactone (SL) subtypes including hirsutinolide and cadinanolide have a controversial genesis. Metabolites of these classes are either described as natural products or as artifacts produced via the influence of solvents, chromatographic mobile phases, and adsorbents used in phytochemical studies. Based on this divergence, and to better understand the sensibility of these metabolites, different pH conditions were used to prepare semisynthetic SLs and evaluate the anti-inflammatory and antiproliferative activities. Therefore, glaucolide B (1) was treated with various Brønsted–Lowry and Lewis acids and bases—the same approach was applied to some of its derivatives—allowing us to obtain 14 semisynthetic SL derivatives, 10 of which are hereby reported for the first time. Hirsutinolide derivatives 7a (CC50 = 5.0 µM; SI = 2.5) and 7b (CC50 = 11.2 µM; SI = 2.5) and the germacranolide derivative 8a (CC50 = 3.1 µM; SI = 3.0) revealed significant cytotoxic activity and selectivity against human melanoma SK-MEL-28 cells when compared with that against non-tumoral HUVEC cells. Additionally, compounds 7a and 7c.1 showed strongly reduced interleukin-6 (IL-6) and nitrite (NOx) release in pre-treated M1 macrophages J774A.1 when stimulated with lipopolysaccharide. Despite the fact that hirsutinolide and cadinanolide SLs may be produced via plant metabolism, this study shows that acidic and alkaline extraction and solid-phase purification processes can promote their formation.

The World Health Organization classifies Leishmania as one of the 17 “neglected diseases” that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be made obsolete by parasite drug resistance. We chose to analyze organoselenides for leishmanicidal potential given the reduced toxicity inherent to selenium and the displayed biological activity of organoselenides against Leishmania. Thus, the biological activities of 77 selenoesters and their N-aryl-propanamide derivatives were predicted using robust in silico models of Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania (Viannia) braziliensis. The models identified 28 compounds with >60% probability of demonstrating leishmanicidal activity against L. infantum, and likewise, 26 for L. amazonesis, 25 for L. braziliensis, and 23 for L. major. The in silico prediction of ADMET properties suggests high rates of oral absorption and good bioavailability for these compounds. In the in silico toxicity evaluation, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology was corroborated with the ensuing experimental validation, which evaluated the inhibition of the Promastigote form of the Leishmania species under study. The activity of the molecules was determined by the IC50 value (µM); IC50 values < 20 µM indicated better inhibition profiles. Sixteen compounds were synthesized and tested for their activity. Eight molecules presented IC50 values < 20 µM for at least one of the Leishmania species under study, with compound NC34 presenting the strongest parasite inhibition profile. Furthermore, the methodology used was effective, as many of the compounds with the highest probability of activity were confirmed by the in vitro tests performed.

Abstract Aspergillus genus causes many diseases, and the species Aspergillus flavus is highly virulent. Treatment of aspergillosis involves azole derivatives such as voriconazole and polyenes such as amphotericin B. Due to an increase in fungal resistance, treatments are now less effective; the search for new compounds with promising antifungal activity has gained importance. The aims of this study were to evaluate the effects of the synthetic amide 2-chloro-N-phenylacetamide (A1Cl) against strains of Aspergillus flavus and to elucidate its mechanism of action. Thus, the minimum inhibitory concentration, minimum fungicidal concentration, conidial germination, associations with antifungal agents, cell wall activities, membrane activities and molecular docking were evaluated. A1Cl presented antifungal activity against Aspergillus flavus strains with a minimum inhibitory concentration of between 16 and 256 μg/mL and a minimum fungicidal concentration between 32 and 512 μg/mL. The minimum inhibitory concentration of A1Cl also inhibited conidial germination, but when associated with amphotericin B and voriconazole, it promoted antagonistic effects. Binding to ergosterol on the fungal plasma membrane is the likely mechanism of action, along with possible inhibition of DNA synthesis through the inhibition of thymidylate synthase. It is concluded that the amide 2-chloro-N-phenylacetamide has promising antifungal potential.

Eriocaulaceae is a pantropical family whose main center of biodiversity is in Brazil. In general, the family has about 1200 species, in which phytochemical and biological studies have shown a variety of structures and activities. The aim of this research is to compile the compounds isolated in the Eriocaulaceae family and carry out a computational study on their biological targets. The bibliographic research was carried out on six databases. Tables were built and organized according to the chemical class. In addition, a summary of the methods of isolating the compounds was also made. In the computational study were used ChEMBL platform, DRAGON 7.0, and the KNIME 4.4.0 software. Two hundred and twenty-two different compounds have been isolated in sixty-eight species, divided mainly into flavonoids and naphthopyranones, and minor compounds. The ligand-based virtual screening found promising molecules and molecules with multitarget potential, such as xanthones 194, 196, 200 and saponin 202, with xanthone 194 as the most promising. Several compounds with biological activities were isolated in the family, but the chemical profiles of many species are still unknown. The selected structures are a starting point for further studies to develop new antiparasitic and antiviral compounds based on natural products.

Parasitic diseases remain as unresolved health issues worldwide. While for some parasites the treatments involve drug combinations with serious side effects, for others, chemical therapies are inefficient due to the emergence of drug resistance. This urges the search for novel antiparasitic agents able to act through multiple mechanisms of action. Here, we report the first multi-target model based on quantitative structure-activity relationships and a multilayer perceptron neural network (mt-QSAR-MLP) to virtually design and predict versatile inhibitors of proteins involved in the survival and/or infectivity of different pathogenic parasites. The mt-QSAR-MLP model exhibited high accuracy (>80%) in both training and test sets for the classification/prediction of protein inhibitors. Several fragments were directly extracted from the physicochemical and structural interpretations of the molecular descriptors in the mt-QSAR-MLP model. Such interpretations enabled the generation of four molecules that were predicted as multi-target inhibitors against at least three of the five parasitic proteins reported here with two of the molecules being predicted to inhibit all the proteins. Docking calculations converged with the mt-QSAR-MLP model regarding the multi-target profile of the designed molecules. The designed molecules exhibited drug-like properties, complying with Lipinski’s rule of five, as well as Ghose’s filter and Veber’s guidelines.

Essential oils (EOs) are a mixture of chemical compounds with a long history of use in food, cosmetics, perfumes, agricultural and pharmaceuticals industries. The main object of this study was to find chemical patterns between 45 EOs and antiprotozoal activity (antiplasmodial, antileishmanial and antitrypanosomal), using different machine learning algorithms. In the analyses, 45 samples of EOs were included, using unsupervised Self-Organizing Maps (SOM) and supervised Random Forest (RF) methodologies. In the generated map, the hit rate was higher than 70% and the results demonstrate that it is possible find chemical patterns using a supervised and unsupervised machine learning approach. A total of 20 compounds were identified (19 are terpenes and one sulfur-containing compound), which was compared with literature reports. These models can be used to investigate and screen for bioactivity of EOs that have antiprotozoal activity more effectively and with less time and financial cost.

Abstract We aimed to evaluate the orofacial antinociceptive effect of geraniol in mice and its molecular anchorage mechanism. Seven mice per group (probabilistic sample) were treated with geraniol (12.5, 25 and 50 mg/kg, i.p.), morphine (6 mg/kg, i.p.) and vehicle (saline + Tween 80 at 0.2%, i.p.) 30 minutes prior to the beginning of the experiment. Injecting glutamate (25 μM), capsaicin (2.5 μg) and formalin (2%) into the right upper lip (perinasal) of the mouse induced nociception. Behavioral analysis of the animals considered the friction time (in seconds) of the mentioned region using hind or front paws by a researcher blinded to the treatment groups. The statistical analysis was performed blindly, considering α = 5%. The results showed that in the glutamate and capsaicin tests, concentrations of 25 mg/kg and 50 mg/kg presented antinociceptive activity (p < 0.005, power> 80%). In the formalin test, geraniol was able to reduce nociception at a concentration of 50 mg/kg (p < 0.005, power> 80%). In the molecular anchorage study, high values of binding between the evaluated substance and receptors of glutamate were observed (metabotropic glutamate receptor, -87.8501 Kcal/mol; N-methyl-D-aspartate, -86.4451 Kcal/mol; α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, -85.6755 Kcal/mol). Geraniol presented orofacial antinociceptive activity, probably by interacting with glutamate-related receptors.

IntroductionPain is considered an unpleasant sensory and emotional experience, being considered as one of the most important causes of human suffering. Computational chemistry associated with bioinformatics has stood out in the process of developing new drugs, through natural products, to manage this condition.ObjectiveTo analyze, through literature data, recent molecular coupling studies on the antinociceptive activity of essential oils and monoterpenes.Data sourceSystematic search of the literature considering the years of publications between 2005 and December 2019, in the electronic databases PubMed and Science Direct.Eligibility CriteriaWere considered as criteria of 1) Biological activity: non-clinical effects of an OE and/or monoterpenes on antinociceptive activity based on animal models and in silico analysis, 2) studies with plant material: chemically characterized essential oils and/or their constituents isolated, 3) clinical and non-clinical studies with in silico analysis to assess antinociceptive activity, 4) articles published in English. Exclusion criteria were literature review, report or case series, meta-analysis, theses, dissertations, and book chapter.ResultsOf 16,006 articles, 16 articles fulfilled all the criteria. All selected studies were non-clinical. The most prominent plant families used were Asteraceae, Euphorbiaceae, Verbenaceae, Lamiaceae, and Lauraceae. Among the phytochemicals studied were α-Terpineol, 3-(5-substituted-1,3,4-oxadiazol-2-yl)-N′-[2-oxo-1,2-dihydro-3H-indol-3-ylidene] propane hydrazide, β-cyclodextrin complexed with citronellal, (−)-α-bisabolol, β-cyclodextrin complexed with farnesol, and p-Cymene. The softwares used for docking studies were Molegro Virtual Docker, Sybyl®X, Vlife MDS, AutoDock Vina, Hex Protein Docking, and AutoDock 4.2 in PyRx 0.9. The molecular targets/complexes used were Nitric Oxide Synthase, COX-2, GluR2-S1S2, TRPV1, β-CD complex, CaV1, CaV2.1, CaV2.2, and CaV2.3, 5-HT receptor, delta receptor, kappa receptor, and MU (μ) receptor, alpha adrenergic, opioid, and serotonergic receptors, muscarinic receptors and GABAA opioid and serotonin receptors, 5-HT3 and M2 receptors. Many of the covered studies used molecular coupling to investigate the mechanism of action of various compounds, as well as molecular dynamics to investigate the stability of protein-ligand complexes.ConclusionsThe studies revealed that through the advancement of more robust computational techniques that complement the experimental studies, they may allow some notes on the identification of a new candidate molecule for therapeutic use.

Background: Due to laboratory logistic issues, our center has traditionally scheduled peripheral blood stem cell harvests based on timing from the start of mobilization. This has proved to be useful in some cases, but also resulted in many fruitless harvests due to poor mobilization. In order to improve the efficiency of collections and compare the effectiveness of peripheral blood CD34+ cells as a predictor with data from other reports, this study analyzed the implementation of this routine. Methods: Peripheral blood and leukapheresis samples were quantified by flow cytometry and the association between these parameters was assessed. Results: Sixty-six consecutive leukapheresis samples were collected from 34 patients after the collection of peripheral blood samples for CD34+ quantification. A moderate positive correlation was observed between peripheral blood CD34+ cell count and total CD34+ cell count/kg (r = 0.596; p-value

Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.

The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, an in-house database of 360 kauranes (tetracyclic diterpenes) was generated, and a combined ligand- and structure-based virtual screening (VS) approach was performed to select potential inhibitors of Leishmania major (Lm) pteridine reductase I (PTR1). The best-ranked kauranes were employed to verify the validity of the VS approach through LmPTR1 enzyme inhibition assay. The half-maximal inhibitory concentration (IC50) values of selected bioactive compounds were examined using the random forest (RF) model (i.e., 2β-hydroxy-menth-6-en-5β-yl ent-kaurenoate (135) and 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid (302)) were below 10 μM. A compound similar to 302, 3α-p-coumaroyloxy-ent-kaur-16-en-19-oic acid (302a), was also synthesized and showed the highest activity against LmPTR1. Finally, molecular docking calculations and molecular dynamics simulations were performed for the VS-selected, most-active kauranes within the active sites of PTR1 hybrid models, generated from three Leishmania species that are known to cause cutaneous leishmaniasis in the new world (i.e., L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes to other species-dependent variants of this enzyme.

Resumo OBJETIVO Descrever a implantação de um indicador de qualidade assistencial associado ao diagnóstico de enfermagem de pacientes com alto risco de sangramento, com base nos resultados alarmantes de tempo de protombina (TP), tempo de tromboplastina parcialmente ativada (TTPa) e plaquetas. MÉTODOS Relato de experiência retrospectivo de ações multidisciplinares desenvolvidas em um hospital universitário. As etapas do estudo envolveram reuniões de equipes, busca de estratégias de comunicação efetiva e criação de um novo indicador de qualidade assistencial. RESULTADOS O indicador foi denominado “Conformidade do Diagnóstico de Enfermagem Risco de Sangramento”, monitorado mensalmente desde junho de 2016. A ficha técnica contempla as características e atributos do indicador. Com base nas suas análises são estabelecidos planos de ações para sua qualificação. CONCLUSÃO A implantação do indicador de qualidade assistencial associado ao diagnóstico de enfermagem aprimorou o processo de comunicação, monitoramento e cuidado de enfermagem a pacientes com risco de sangramento.

The pharmaceutical industry is increasingly joining chemoinformatics in the search for the development of new drugs to be used in the treatment of diseases. These computational studies have the advantage of being less expensive and optimize the study time, and thus the interest in this area is increasing. Among the techniques used is the development of multitarget directed ligands (MTDLs), which has become an ascending technique, mainly due to the improvement in the quality of treatment involving several drugs. Multitarget therapy is more effective than traditional drug therapy that emphasizes maximum selectivity for a single target. In this review a multitarget drug survey was carried out as a promising strategy in several important diseases: neglected diseases, neurodegenerative diseases, AIDS, and cancer. In addition, we discuss Computer-Aided Drug Design (CADD) techniques as a tool in the projection of multitarget compounds against these diseases.

Background: The growing demand for agricultural products has led to the misuse/overuse of insecticides; resulting in the use of higher concentrations and the need for ever more toxic products. Ecologically, bioinsecticides are considered better and safer than synthetic insecticides; they must be toxic to the target organism, yet with low or no toxicity to non-target organisms. Many plant extracts have seen their high insecticide potential confirmed under laboratory conditions, and in the search for plant compounds with bioinsecticidal activity, the Lamiaceae family has yielded satisfactory results. Objective: The aim of our study was to develop computer-assisted predictions for compounds with known insecticidal activity against Aphis gossypii and Drosophila melanogaster. Results and conclusion: Structure analysis revealed ent-kaurane, kaurene, and clerodane diterpenes as the most active, showing excellent results. We also found that the interactions formed by these compounds were more stable, or presented similar stability to the commercialized insecticides tested. Overall, we concluded that the compounds bistenuifolin L (1836) and bistenuifolin K (1931), were potentially active against A. gossypii enzymes; and salvisplendin C (1086) and salvixalapadiene (1195), are potentially active against D. melanogaster. We observed and highlight that the diterpenes bistenuifolin L (1836), bistenuifolin K (1931), salvisplendin C (1086), and salvixalapadiene (1195), present a high probability of activity and low toxicity against the species studied.

Objective: This study evaluated the antifungal activity of cinnamaldehyde on Candida spp. In vitro and in situ assays were carried out to test cinnamaldehyde for its anti-Candida effects, antibiofilm activity, effects on fungal micromorphology, antioxidant activity, and toxicity on keratinocytes and human erythrocytes. Statistical analysis was performed considering α = 5%. Results: The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of cinnamaldehyde ranged from 18.91 μM to 37.83 μM. MIC values did not change in the presence of 0.8 M sorbitol, whereas an 8-fold increase was observed in the presence of ergosterol, suggesting that cinnamaldehyde may act on the cell membrane, which was subsequently confirmed by docking analysis. The action of cinnamaldehyde likely includes binding to enzymes involved in the formation of the cytoplasmic membrane in yeast cells. Cinnamaldehyde-treated microcultures showed impaired cellular development, with an expression of rare pseudo-hyphae and absence of chlamydoconidia. Cinnamaldehyde reduced biofilm adherence by 64.52% to 33.75% (p < 0.0001) at low concentrations (378.3–151.3 µM). Cinnamaldehyde did not show antioxidant properties. Conclusions: Cinnamaldehyde showed fungicidal activity through a mechanism of action likely related to ergosterol complexation; it was non-cytotoxic to keratinocytes and human erythrocytes and showed no antioxidant activity.

Isougenol is a phytoconstituent found in several essential oils. Since many natural products are potent antimicrobials, the synthesis of hybrid molecules—combining the chemical skeleton of the phytochemical with synthetic groups—can generate substances with enhanced biological activity. Based on this, the objective of this study was to evaluate the antifungal activity of isoeugenol and hybrid acetamides against Candida albicans isolated from the oral cavity. The methodologies used were the determination of minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), action on fungal micromorphology, interaction test with nystatin by the checkerboard method and molecular docking study with important enzymes in the maintenance of fungal viability. The synthetic molecules did not demonstrate significant antifungal activity in vitro. The isoeugenol MIC and MFC varied between 128 and 256 µg/mL, being the phytoconstituent able to interfere in the formation of blastoconid and chlamydoconid structures, important in the pathogenic process of the species. The molecular docking study revealed that isoeugenol is a potential inhibitor of the enzymes 14-α-demethylase and delta-14-sterol reductase, interfering in the fungal cell membrane biosynthesis. Thus, this research provides clearer expectations for future pharmacological studies with isoeugenol and derived molecules, aiming at its therapeutic application against infections caused by Candida spp.

Leishmaniasis is endemic in at least 98 countries. Due to the high toxicity and resistance associated with the drugs, we chose lignans as an alternative, due to their favorable properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET). To investigate their leishmanicidal potential, the biological activities of a set of 160 lignans were predicted using predictive models that were built using data for Leishmania major and L. (Viannia) braziliensis. A combined analysis, based on ligand and structure, and several other computational approaches were used. The results showed that the combined analysis was able to select 11 lignans with potential activity against L. major and 21 lignans against L. braziliensis, with multitargeting effects and low or no toxicity. Of these compounds, four were isolated from the species Justicia aequilabris (Nees) Lindau. All of the identified compounds were able to inhibit the growth of L. braziliensis promastigotes, with the most active compound, (159) epipinoresinol-4-O-β-d-glucopyranoside, presenting an IC50 value of 5.39 µM and IC50 value of 36.51 µM for L. major. Our findings indicated the potential of computer-aided drug design and development and demonstrated that lignans represent promising prototype compounds for the development of multitarget drugs against leishmaniasis.

Cancer is a life-threatening disease killing millions of people globally. Among various medical treatments, nano-medicines are gaining importance continuously. Many nanocarriers have been developed for treatment, but polymerically-based ones are acquiring importance due to their targeting capabilities, biodegradability, biocompatibility, capacity for drug loading and long blood circulation time. The present article describes progress in polymeric nano-medicines for theranostic cancer treatment, which includes cancer diagnosis and treatment in a single dosage form. The article covers the applications of natural and synthetic polymers in cancer diagnosis and treatment. Efforts were also made to discuss the merits and demerits of such polymers; the status of approved nano-medicines; and future perspectives.

Background: Thymol and carvacrol have previously demonstrated larvicidal activity against Aedes aegypti (Diptera: Culicidae). In view of this fact, it was of our interest to obtain synthetic derivatives and evaluate their larvicidal ac­tivity on Ae. aegypti larvae. Methods: Structural modifications were performed on thymol and carvacrol in an effort to understand the functional groups necessary for modulating their activities and to lead possibly to more effective larvae control agents. The derivatives were further subjected to SAR and computational studies (molecular modeling and chemometric tools (CPCA and PCA)) to extract structural information regarding their larvicidal properties. Field collected and Rocke­feller populations of Ae. aegypti were used. Results: Carvacrol and thymol exhibited LC50 of 51 and 58ppm for field collected larvae, respectively. Carvacrol derivatives exhibited LC50 ranging from 39 to 169ppm, while thymol derivatives exhibited LC50 ranging from 18 to 465ppm. Substitution of the acidic proton of carvacrol by esters, ethers, and acetic acid resulted in either mainte­nance or reduction of potency. Conclusion: Thymol derivatives were, to a certain extent, more efficient larvicides against Ae. aegypti than carvacrol derivatives, particularly to Rockefeller larvae. The chemometrics tools applied in this study showed that the inde­pendent variables indicate a mixed profile. Nevertheless, hydrophobic interactions increased the larvicidal activity.

Lamiaceae is one of the largest families of angiosperms and is classified into 12 subfamilies that are composed of 295 genera and 7775 species. It presents a variety of secondary metabolites such as diterpenes that are commonly found in their species, and some of them are known to be chemotaxonomic markers. The aim of this work was to construct a database of diterpenes and to use it to perform a chemotaxonomic analysis among the subfamilies of Lamiaceae, using molecular descriptors and self-organizing maps (SOMs). The 4115 different diterpenes corresponding to 6386 botanical occurrences, which are distributed in eight subfamilies, 66 genera, 639 different species and 4880 geographical locations, were added to SistematX. Molecular descriptors of diterpenes and their respective botanical occurrences were used to generate the SOMs. In all obtained maps, a match rate higher than 80% was observed, demonstrating a separation of the Lamiaceae subfamilies, corroborating with the morphological and molecular data proposed by Li et al. Therefore, through this chemotaxonomic study, we can predict the localization of a diterpene in a subfamily and assist in the search for secondary metabolites with specific structural characteristics, such as compounds with potential biological activity.

The increased incidence of opportunistic fungal infections, associated with greater resistance to the antifungal drugs currently in use has highlighted the need for new solutions. In this study twenty four coumarin derivatives were screened in vitro for antifungal activity against strains of Aspergillus. Some of the compounds exhibited significant antifungal activity with MICs values ranging between 16 and 32 µg/mL. The structure-activity relationships (SAR) study demonstrated that O-substitutions are essential for antifungal activity. It also showed that the presence of a short aliphatic chain and/or electron withdrawing groups (NO2 and/or acetate) favor activity. These findings were confirmed using density functional theory (DFT), when calculating the LUMO density. In Principal Component Analysis (PCA), two significant principal components (PCs) explained more than 60% of the total variance. The best Partial Least Squares Regression (PLS) model showed an r2 of 0.86 and q2cv of 0.64 corroborating the SAR observations as well as demonstrating a greater probe N1 interaction for active compounds. Descriptors generated by TIP correlogram demonstrated the importance of the molecular shape for antifungal activity.

Semisynthetic and commercial coumarins were investigated for their antibacterial and adjuvant properties with antibiotic agents against norfloxacin, erythromycin, and tetracycline resistant Staphylococcus aureus as based on efflux mechanisms. The coumarins and certain commercial antibiotics had their Minimum Inhibitory Concentrations determined by broth microdilution assay against resistant S. aureus strains which overexpress efflux pump proteins. For evaluation of the modulatory activity, the antibiotics MICs were determined in the presence of the coumarin derivatives at subinhibitory concentration. Although the coumarins did not display relevant antibacterial activity (MIC ≥ 128 µg/mL), they did modulate the antibiotics activities. Various coumarins, especially the alkylated derivatives in combination with antibiotics at subinhibitory concentrations, modulated antibiotic activity, reducing the MIC for tetracycline and norfloxacin by 2 to 8 times. Polar Surface Area (PSA) studies were performed and the fact that the presence of apolar groups is an important factor for the modulatory activity of coumarins was corroborated. Docking on the Penicillin-Binding Protein from MRSA identified that 18 is a potential ligand presenting low Ebinding. The results indicate that coumarin derivatives modulated antibiotic resistance and may be used as potential antibiotic adjuvants, acting by bacterial efflux pump inhibition in S. aureus.

Cancer is a major public health problem with limited success of available treatments, pointing to the need for new strategies to be developed. Phosphoethanolamine exhibits broad antitumor activity in a variety of tumor cells and potent inhibitor effects on tumor progress in vivo. Once-used organophosphates inhibit acetylcholinesterase (AChE), resulting in toxic effects to the user. As this group is present in phosphoethanolamine, we perform prediction of the in silico metabolism of phosphoethanolamine and submit this series to a docking study on AChE. A total of 10 metabolites were indicated by the prediction, including ammonia and hydroxylamine, which were not included in the study. Using a group of 8 organophosphorus whose pIC50 values ranged from 5.92 to 9.47 as template, we observed that no compound present in the phosphoethanolamine series had a binding energy lower than that of organophosphorus, suggesting that the series has low inhibitory power on AChE. In light of this, we conclude that phosphoethanolamine and its predicted metabolites do not significantly inhibit AChE to cause a cholinergic crisis. This finding highlights the importance of investigating this compound as lead for potential anticancer agents.

The Asteraceae, one of the largest families among angiosperms, is chemically characterised by the production of sesquiterpene lactones (SLs). A total of 1,111 SLs, which were extracted from 658 species, 161 genera, 63 subtribes and 15 tribes of Asteraceae, were represented and registered in two dimensions in the SISTEMATX, an in-house software system, and were associated with their botanical sources. The respective 11 block of descriptors: Constitutional, Functional groups, BCUT, Atom-centred, 2D autocorrelations, Topological, Geometrical, RDF, 3D-MoRSE, GETAWAY and WHIM were used as input data to separate the botanical occurrences through self-organising maps. Maps that were generated with each descriptor divided the Asteraceae tribes, with total index values between 66.7% and 83.6%. The analysis of the results shows evident similarities among the Heliantheae, Helenieae and Eupatorieae tribes as well as between the Anthemideae and Inuleae tribes. Those observations are in agreement with systematic classifications that were proposed by Bremer, which use mainly morphological and molecular data, therefore chemical markers partially corroborate with these classifications. The results demonstrate that the atom-centred and RDF descriptors can be used as a tool for taxonomic classification in low hierarchical levels, such as tribes. Descriptors obtained through fragments or by the two-dimensional representation of the SL structures were sufficient to obtain significant results, and better results were not achieved by using descriptors derived from three-dimensional representations of SLs. Such models based on physico-chemical properties can project new design SLs, similar structures from literature or even unreported structures in two-dimensional chemical space. Therefore, the generated SOMs can predict the most probable tribe where a biologically active molecule can be found according Bremer classification.

Fifty 2-[(arylidene)amino]-4,5-cycloalkyl[b]thiophene-3-carbonitrile derivatives were screened for their in vitro antifungal activities against Candida krusei and Cryptococcus neoformans. Based on experimentally determined minimum inhibitory concentration (MIC) values, we conducted computer-aided drug design studies [molecular modelling, chemometric tools (CPCA, PCA, PLS) and QSAR-3D] that enable the prediction of three-dimensional structural characteristics that influence the antifungal activities of these derivatives. These predictions provide direction with regard to the syntheses of new derivatives with improved biological activities, which can be used as therapeutic alternatives for the treatment of fungal infections.

The Annonaceae family is distributed throughout Neotropical regions of the world. In Brazil, it covers nearly all natural formations particularly Annona, Xylopia and Polyalthia and is characterized chemically by the production of sources of terpenoids (mainly diterpenes), alkaloids, steroids, polyphenols and, flavonoids. Studies from 13C NMR data of diterpenes related with their botanical occurrence were used to generate self-organizing maps (SOM). Results corroborate those in the literature obtained from morphological and molecular data for three genera and the model can be used to project other diterpenes. Therefore, the model produced can predict which genera are likely to contain a compound.

In this study, the antinociceptive properties of 3,4-dihydro-2,6-diaryl-4-oxo-pyrimidine-5-carbonitrile derivatives 5a–i at doses of 25 and 50 mg/kg were evaluated in mice, using the abdominal constriction test. Molecular modeling studies were also performed using density functional theory calculations. These data provided information about the electrostatic and ionization potentials and were used to compare the antinociceptive activity of the title compounds. The most active compounds were 3,4-dihydro-2-(4-chlorophenyl)-6-(4-methoxyphenyl)-4-oxo-pyrimidine-5-carbonitrile (5b) and 3,4-dihydro-2,6-diphenyl-4-oxo-pyrimidine-5-carbonitrile (5i), which inhibited the number of abdominal constrictions, at 50 mg/kg dose, in 88.6% and 88% of the sample, respectively. A preliminary SAR study demonstrated that halogen replacement in the phenyl rings of the compounds under study reduces the antinociceptive activity. DFT calculations showed that there is a high correlation between the ionization potentials and the analgesic properties of the compounds. It was found that compounds with a positive ionization potential (compounds 5b and 5i) were found to be the best analgesic drugs in this series.

Tissue damage due to oxidative stress is directly linked to development of many, if not all, human morbidity factors and chronic diseases. In this context, the search for dietary natural occurring molecules with antioxidant activity, such as flavonoids, has become essential. In this study, we investigated a set of 41 flavonoids (23 flavones and 18 flavonols) analyzing their structures and biological antioxidant activity. The experimental data were submitted to a QSAR (quantitative structure-activity relationships) study. NMR 13C data were used to perform a Kohonen self-organizing map study, analyzing the weight that each carbon has in the activity. Additionally, we performed MLR (multilinear regression) using GA (genetic algorithms) and molecular descriptors to analyze the role that specific carbons and substitutions play in the activity.Danos aos tecidos devido ao estresse oxidativo estão diretamente ligados ao desenvolvimento de muitos, senão todos, os fatores de sedentarismo e de doenças crônicas. Neste contexto, a busca de moléculas naturais, que participam da nossa dieta e que possuam atividade antioxidante, flavonóides, torna-se de grande interesse. Neste estudo, nós investigamos um conjunto de 41 flavonóides (23 flavonas e 18 flavonóis), relacionando suas estruturas e atividade antioxidante. Os dados experimentais foram submetidos à análise de QSAR (relações quantitativas estrutura-atividade). Dados de RMN 13C foram utilizados para realizar um estudo do mapa auto-organizável de Kohonen, analisando o peso que cada carbono tem na atividade. Além disso, realizamos uma MLR (regressão múltipla) usando GA (algoritmos genéticos) e descritores moleculares para avaliar a influência de carbonos e substituições na atividade.

Natural products have widespread biological activities, including inhibition of mitochondrial enzyme systems. Some of these activities, for example cytotoxicity, may be the result of alteration of cellular bioenergetics. Based on previous computer-aided drug design (CADD) studies and considering reported data on structure-activity relationships (SAR), an assumption regarding the mechanism of action of natural products against parasitic infections involves the NADH-oxidase inhibition. In this study, chemometric tools, such as: Principal Component Analysis (PCA), Consensus PCA (CPCA), and partial least squares regression (PLS), were applied to a set of forty natural compounds, acting as NADH-oxidase inhibitors. The calculations were performed using the VolSurf+ program. The formalisms employed generated good exploratory and predictive results. The independent variables or descriptors having a hydrophobic profile were strongly correlated to the biological data.

The traditional work of a natural products researcher consists in large part of time-consuming experimental work, collecting biota to prepare and analyze extracts and to identify innovative metabolites. However, along this long scientific path, much information is lost or restricted to a specific niche. The large amounts of data already produced and the science of metabolomics reveal new questions: Are these compounds known or new? How fast can this information be obtained? To answer these and other relevant questions, an appropriate procedure to correctly store information on the data retrieved from the discovered metabolites is necessary. The SistematX (http://sistematx.ufpb.br) interface is implemented considering the following aspects: (a) the ability to search by structure, SMILES (Simplified Molecular-Input Line-Entry System) code, compound name and species; (b) the ability to save chemical structures found by searching; (c) compound data results include important characteristics for natural products chemistry; and (d) the user can find specific information for taxonomic rank (from family to species) of the plant from which the compound was isolated, the searched-for molecule, and the bibliographic reference and Global Positioning System (GPS) coordinates. The SistematX homepage allows the user to log into the data management area using a login name and password and gain access to administration pages. In this article, we introduced a modern and innovative web interface for the management of a secondary metabolite database. With its multiplatform design, it is able to be properly consulted via the internet and managed from any accredited computer. The interface provided by SistematX contains a wealth of useful information for the scientific community about natural products, highlighting the locations of species from which compounds are isolated.

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies.

ABSTRACT Introduction: The immature platelet and immature reticulocyte fractions represent the ratios of platelets and reticulocytes recently released into the circulation and thus with higher RNA content. They are considered early indicators of bone marrow recovery. Objective: The aim of this study was to determine the reference ranges for the immature platelet and reticulocyte fractions of hematologically normal individuals in a university hospital. Methods: Venous blood samples collected in ethylenediaminetetraacetic acid K3 were analyzed using a Sysmex XE-5000™ analyzer. Individuals with platelet and reticulocyte counts within the reference ranges, and a blood count within the laboratory's screening criteria were included. Individuals with clinical conditions that could affect hematological results were excluded. The immature platelet fraction, high, medium and low fluorescence reticulocyte fractions and reticulocyte hemoglobin equivalent were evaluated. The reference ranges were determined according to the recommendations of the International Federation of Clinical Chemistry. Results: One hundred and thirty-two outpatients were evaluated. The mean age was 44 years (range: 13-80 years), 72 (54.5%) were women treated in a university hospital. The mean platelet count was 250.8 × 109/L and the mean reticulocyte count was 0.052 × 109/L. The following reference ranges were obtained: immature reticulocyte fraction 1.6-12.1%, the high, medium and low fluorescence reticulocyte fractions were 0.0-1.7%, 1.6-11.0% and 87.9-98.4%, respectively, the reticulocyte hemoglobin equivalent was 30.0-37.6% and immature platelet fraction was 0.8-5.6%. There was a statistically significant difference (p-value = 0.006) between genders in respect to the immature platelet fraction with 0.8-4.7% for females and 0.7-6.1% for males. The immature reticulocyte fraction was directly correlated with the reticulocyte count. Conclusion: Determining the reference range is critical to the introduction of a new parameter. The reference ranges obtained herein corroborate those reported in previous publications and will contribute to the clinical and laboratory application of the indices.