Viruses, including influenza viruses, MERS-CoV (Middle East respiratory syndrome coronavirus), SARS-CoV (severe acute respiratory syndrome coronavirus), HAV (Hepatitis A virus), HBV (Hepatitis B ...virus), HCV (Hepatitis C virus), HIV (human immunodeficiency virus), EBOV (Ebola virus), ZIKV (Zika virus), and most recently SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), are responsible for many diseases that result in hundreds of thousands of deaths yearly. The ongoing outbreak of the COVID-19 disease has raised a global concern and intensified research on the detection of viruses and virus-related diseases. Novel methods for the sensitive, rapid, and on-site detection of pathogens, such as the recent SARS-CoV-2, are critical for diagnosing and treating infectious diseases before they spread and affect human health worldwide. In this sense, electrochemical impedimetric biosensors could be applied for virus detection on a large scale. This review focuses on the recent developments in electrochemical-impedimetric biosensors for the detection of viruses.
Research efforts are placing an ever increasing emphasis on identifying signal transduction pathways related to the chemopreventive activity of curcumin. Its anticarcinogenic effects are presumably ...mediated by the regulation of signaling cascades, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), and mitogen-activated protein kinases (MAPK). By modulating signal transduction pathways, curcumin induces apoptosis in malignant cells, thus inhibiting cancer development and progression. Due to the lack of mechanistic insight in the scientific literature, we developed a novel inverse molecular docking protocol based on the CANDOCK algorithm. For the first time, we performed inverse molecular docking of curcumin into a collection of 13,553 available human protein structures from the Protein Data Bank resulting in prioritized target proteins of curcumin. Our predictions were in agreement with the scientific literature and confirmed that curcumin binds to folate receptor β, DNA (cytosine-5)-methyltransferase 3A, metalloproteinase-2, mitogen-activated protein kinase 9, epidermal growth factor receptor and apoptosis-inducing factor 1. We also identified new potential protein targets of curcumin, namely deoxycytidine kinase, NAD-dependent protein deacetylase sirtuin-1 and -2, ecto-5'-nucleotidase, core histone macro-H2A.1, tyrosine-protein phosphatase non-receptor type 11, macrophage colony-stimulating factor 1 receptor, GTPase HRas, aflatoxin B1 aldehyde reductase member 3, aldo-keto reductase family 1 member C3, amiloride-sensitive amine oxidase, death-associated protein kinase 2 and tryptophan-tRNA ligase, that may all play a crucial role in its observed anticancer effects. Moreover, our inverse docking results showed that curcumin potentially binds also to the proteins cAMP-specific 3',5'-cyclic phosphodiesterase 4D and 17-β-hydroxysteroid dehydrogenase type 10, which provides a new explanation for its efficiency in the treatment of Alzheimer's disease. We firmly believe that our computational results will complement and direct future experimental studies on curcumin's anticancer activity as well as on its therapeutic effects against Alzheimer's disease.
Being secondary plant metabolites, polyphenols represent a large and diverse group of substances abundantly present in a majority of fruits, herbs and vegetables. The current contribution is focused ...on their bioavailability, antioxidative and anticarcinogenic properties. An overview of extraction methods is also given, with supercritical fluid extraction highlighted as a promising eco-friendly alternative providing exceptional separation and protection from degradation of unstable polyphenols. The protective role of polyphenols against reactive oxygen and nitrogen species, UV light, plant pathogens, parasites and predators results in several beneficial biological activities giving rise to prophylaxis or possibly even to a cure for several prevailing human diseases, especially various cancer types. Omnipresence, specificity of the response and the absence of or low toxicity are crucial advantages of polyphenols as anticancer agents. The main problem represents their low bioavailability and rapid metabolism. One of the promising solutions lies in nanoformulation of polyphenols that prevents their degradation and thus enables significantly higher concentrations to reach the target cells. Another, more practiced, solution is the use of mixtures of various polyphenols that bring synergistic effects, resulting in lowering of the required therapeutic dose and in multitargeted action. The combination of polyphenols with existing drugs and therapies also shows promising results and significantly reduces their toxicity.
Advances in computer hardware and the availability of high-performance supercomputing platforms and parallel computing, along with artificial intelligence methods are successfully complementing ...traditional approaches in medicinal chemistry. In particular, machine learning is gaining importance with the growth of the available data collections. One of the critical areas where this methodology can be successfully applied is in the development of new antibacterial agents. The latter is essential because of the high attrition rates in new drug discovery, both in industry and in academic research programs. Scientific involvement in this area is even more urgent as antibacterial drug resistance becomes a public health concern worldwide and pushes us increasingly into the post-antibiotic era. In this review, we focus on the latest machine learning approaches used in the discovery of new antibacterial agents and targets, covering both small molecules and antibacterial peptides. For the benefit of the reader, we summarize all applied machine learning approaches and available databases useful for the design of new antibacterial agents and address the current shortcomings.
Rosemary (
Rosmarinus officinalis
L.) of the
Lamiaceae
family represents an evergreen medicinal plant with various health-promoting pharmacological effects. This paper provides a complete overview of ...diverse biological activities of rosemary extracts, essential oils as well as their numerous bioactive compounds, ranging from antioxidative, anti-inflammatory, and antimicrobial over cognitive enhancing to their anticarcinogenic effects. In addition, state of the art extraction, distillation, fractionation, and characterization techniques for obtaining high-quality rosemary extracts and essential oils as well as methods for determining their antioxidative, antimicrobial, anti-inflammatory, and anticarcinogenic potentials are also presented. Finally, new ideas for future computational studies on chemical reactivities and binding affinities of health-promoting rosemary compounds together with suggestions for their improved bioavailability through diverse encapsulation techniques are introduced.
6-Gingerol from ginger has received considerable attention as a potential cancer therapeutic agent because of its chemopreventive and chemotherapeutic effects, as well as its safety. In the current ...study, we examined 6-gingerol as a natural scavenger of nine ultimate chemical carcinogens to which we are frequently exposed: glycidamide, styrene oxide, aflatoxin B1 exo-8,9-epoxide,
-propiolactone, ethylene oxide, propylene oxide, 2-cyanoethylene oxide, chloroethylene oxide, and vinyl carbamate epoxide. To evaluate 6-gingerol efficacy, we expanded our research with the examination of glutathione-the strongest natural scavenger in human cells. The corresponding activation free energies were calculated using Hartree-Fock method with three flexible basis sets and two implicit solvation models. According to our results, 6-gingerol proves to be an extremely effective scavenger of chemical carcinogens of the epoxy type. On the other hand, with the exception of aflatoxin B1 exo-8,9-epoxide, glutathione represents a relatively poor scavenger, whose efficacy could be augmented by 6-gingerol. Moreover, our quantum mechanical study of the alkylation reactions of chemical carcinogens with 6-gingerol and glutathione provide valuable insights in the reaction mechanisms and the geometries of the corresponding transition states. Therefore, we strongly believe that our research forms a solid basis for further computational, experimental and clinical studies of anticarcinogenic properties of 6-gingerol as well as for the development of novel chemoprophylactic dietary supplements. Finally, the obtained results also point to the applicability of quantum chemical methods to studies of alkylation reactions related to chemical carcinogenesis.
Thermal stabilities of DNA duplexes containing Gua (
), α- (
) or β-anomer of formamidopyrimidine-N7-9-hydroxy-aflatoxin B₁ (
) differ markedly (T
: a < g < b ), but the underlying molecular origin ...of this experimentally observed phenomenon is yet to be identified and determined. Here, by employing explicit-solvent molecular dynamics simulations coupled with free-energy calculations using a combined linear-interaction-energy/linear-response-approximation approach, we explain the quantitative differences in T m in terms of three structural features (bulkiness, order, and compactness) and three energetical contributions (non-polar, electrostatic, and preorganized-electrostatic), and thus advance the current understanding of the relationships between structures, free energies, and thermal stabilities of DNA double helices.
SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of
. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We ...performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CL
or M
). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and ({(S)-1-(1H-indol-2-yl)methyl-3-pyrrolidinyl}methyl)amino(5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CL
active site. These compounds will facilitate further 3CL
inhibitor design.
Although one can find numerous studies devoted to the investigation of antioxidative activity of ellagic acid (EA) in the scientific literature, the mechanisms of its action have not yet been fully ...clarified. Therefore, further kinetic studies are needed to understand its antioxidative capacity completely. This work aims to reveal the underlying molecular mechanisms responsible for the antioxidative action of EA. For this purpose, its reactions with HO• and CCl3OO• radicals were simulated at physiological conditions using the quantum mechanics-based test for overall free-radical scavenging activity. The density functional theory in combination with the conductor-like polarizable continuum solvation model was utilized. With HO• radical EA conforms to the hydrogen atom transfer and radical adduct formation mechanisms, whereas sequential proton loss electron transfer mechanism is responsible for scavenging of CCl3OO• radical. In addition, compared to trolox, EA was found more reactive toward HO•, but less reactive toward CCl3OO•. The calculated rate constants for the reactions of EA with both free radicals are in a very good agreement with the corresponding experimental values.
Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates ...inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer's disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin's inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer's disease with a potentially wider therapeutic window and fewer adverse side effects.
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