Secondary metabolites are plant products that occur usually in differentiated cells, generally not being necessary for the cells themselves, but likely useful for the plant as a whole. ...Neurodegeneration can be found in many different levels in the neurons, it always begins at the molecular level and progresses toward the systemic levels. Usually, alterations are observed such as decreasing cholinergic impulse, toxicity related to reactive oxygen species (ROS, inflammatory "amyloid plaque" related processes, catecholamine disequilibrium, etc. Computer aided drug design (CADD has become relevant in the drug discovery process; technological advances in the areas of molecular structure characterization, computational science, and molecular biology have contributed to the planning of new drugs against neurodegenerative diseases. This review discusses scientific CADD studies of the secondary metabolites. Flavonoids, alkaloids, and xanthone compounds have been studied by various researchers (as inhibitory ligands in molecular docking; mainly with three enzymes: acetylcholinesterase (AChE; EC 3.1.1.7, butyrylcholinesterase (BChE; EC 3.1.1.8, and monoamine oxidase (MAO; EC 1.4.3.4. In addition, we have applied ligand-based-virtual screening (using Random Forest, associated with structure-based- virtual screening (docking of a small dataset of 469 alkaloids of the Apocynaceae family from an in-house data bank to select structures with potential inhibitory activity against human AChE. This computer-aided drug design study selected certain alkaloids that might be useful in further studies for the treatment of neurological disorders such as Alzheimer's and Parkinson's disease.
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.
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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 the Asteraceae family that have presented a wide range of biological activities. From the ChEMBL database, we selected a diverse set of 4452, 1635, and 1322 structures with tested activity against the three T. cruzi parasitic forms: amastigote, trypomastigote, and epimastigote, respectively, to create random forest (RF) models with an accuracy of greater than 74 % for cross‐validation and test sets. Afterward, a ligand‐based virtual screen of the entire SLs of the Asteraceae database stored in SistematX (1306 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.
Attention to the neglected: Chagas disease is a neglected tropical disease that affects more than eight million people in the Americas. Using a set of 1306 sesquiterpene lactones (SLs) obtained from SistematX, ligand‐ and structure‐based virtual screening were performed. Afterward, these two methodologies were combined to select potential antichagasic SLs for the three parasitic forms of T. cruzi, establishing a possible mechanism of action.
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Hybrid Compounds as Direct Multitarget Ligands: A Review de Oliveira Pedrosa, Michelle; Duarte da Cruz, Rayssa Marques; de Oliveira Viana, Jessika ...
Current topics in medicinal chemistry,
04/2017, Volume:
17, Issue:
9
Journal Article
Peer reviewed
Molecular Hybridization is an approach in rational drug design where new chemical entities are obtained by combining two or more pharmacophoric units from different bioactive compounds into a single ...molecule. Through this approach, medicinal chemists hope that the new hybrid derivative presents: better affinity and efficacy when compared to the parent drugs; a modified selectivity profile with improvement over pharmacokinetic and pharmacodynamic restrictions; dual or multiple modes of action; reduction of undesirable side effects; decreases in drug-drug interactions; reduced emergence or spread of drug resistance in microorganisms and protozoans; and lower cost. The approach has been successfully used by many research groups around the world and has had very promising results with diseases having multifactorial profiles, like Alzheimer´s, Parkinson´s disease, cancer, inflammation, and hypertension among others. The purpose of this paper is to conduct an updated review of molecular hybridization and multitarget profiling (a rational drug design approach), and its applications to the design and discovery of novel hybrid compounds with anti-inflammatory, antimicrobial, anticancer and antiprotozoal (leishmaniasis, malaria, and schistosomiasis) activities over the last six years.
This study evaluated the antifungal activity of cinnamaldehyde on
spp. In vitro and in situ assays were carried out to test cinnamaldehyde for its anti-
effects, antibiofilm activity, effects on ...fungal micromorphology, antioxidant activity, and toxicity on keratinocytes and human erythrocytes. Statistical analysis was performed considering α = 5%.
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% (
< 0.0001) at low concentrations (378.3-151.3 µM). Cinnamaldehyde did not show antioxidant properties.
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.
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The critical enzyme dihydrofolate reductase-thymidylate synthase in
(
DHFR-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
DHFR-TS is crucial for the creation of novel anti-
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
DHFR-TS. Through consensus analysis of both approaches, we identified three compounds, i.e., lithospermic acid (
), diarctigenin (
), and isolappaol A (
), 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
DHFR-TS recombinant protein. The test compounds effectively inhibited the enzyme with IC
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'-
-glucoside, and rutin, exhibited low activity against this target. The selective index (SI) for all tested compounds was determined using
DHFR with moderate inhibitory effect. Among these hits, lignans
and
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.
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Alzheimer's disease (AD) is a very common neurodegenerative disorder in individuals over 65 years of age; however, younger individuals can also be affected due to brain damage.
The general symptoms ...of this disease include progressive loss of memory, changes in behavior, deterioration of thinking, and gradual loss of ability to perform daily activities. According to the World Health Organization, dementia has affected more than 50 million people worldwide, and it is estimated that there are 10 million new cases per year, of which 70% are due to AD.
This paper reported a review of scientific articles available on the internet which discuss in silico analyzes such as molecular docking, molecular dynamics, and quantitative structure-activity relationship (QSAR) of different classes of natural products and their derivatives published from 2016 onwards. In addition, this work reports the potential of fermented papaya preparation against oxidative stress in AD.
This research reviews the most recent studies on AD, computational analysis methods used in proposing new bioactive compounds and their possible molecular targets, and finally, the molecules or classes of natural products involved in each study.
Thus, studies like this can orientate new research works on neurodegenerative diseases, especially AD.
Here we report the development of MolPredictX, an innovate and freely accessible web interface for biological activity predictions of query molecules. MolPredictX utilizes in‐house QSAR models to ...provide 27 qualitative predictions (active or inactive), and quantitative probabilities for bioactivity against parasitic (Trypanosoma and Leishmania), viral (Dengue, Sars‐CoV and Hepatitis C), pathogenic yeast (Candida albicans), bacterial (Salmonella enterica and Escherichia coli), and Alzheimer disease enzymes. In this article, we introduce the methodology and usability of this webtool, highlighting its potential role in the development of new drugs against a variety of diseases. MolPredictX is undergoing continuous development and is freely available at https://www.molpredictx.ufpb.br/.
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