Computational Drug Design against Ebola Virus Targeting Viral Matrix Protein VP30

Ebola viral disease (EVD) is a deadly infectious hemorrhagic viral fever caused by the Ebola virus with a high mortality rate. Until date, there is no effective drug or vaccination available to combat this condition. This study focuses on designing an effective antiviral drug for Ebola viral disease targeting viral protein 30 (VP30) of Ebola virus, highly required for transcription initiation. The lead molecules were screened for Lipinski rule of five, ADMET study following which molecular docking and bioactivity prediction was carried out. The compounds with the least binding energy were analyzed using interaction software. The results revealed that 6-Hydroxyluteolin and (-)-Arctigenin represent active lead compounds that inhibit the activity of VP30 protein and exhibits efficient pharmacokinetics. Both these compounds are plant-derived flavonoids and possess no known adverse effects on human health. In addition, they bind strongly to the predicted binding site centered on Lys180, suggesting that these two lead molecules can be imperative in designing a potential drug for EVD

Identification of Potential Ebola Virus Nucleoprotein (EBOV NP) Inhibitor Derivate from Various Traditional Medicinal Plants in Indonesia: in silico study

Ebola virus disease is caused by Ebolavirus infection. Within infection, Ebola nucleoprotein (EBOV NP) is essential part for virus proliferation. Recent report showed that the outbreak was happened in Congo on February 2021. Although million cases were reported, the drug is remain unavailable. However, Indonesia had a high diversity of plants as traditional drugs. This research aimed to identify the traditional drug plants as potential inhibitor for EBOV NP. The SMILE notation of 65 identified compounds were collected from PubChem and 3D structured of EBOV NP (PDB ID: 4Z9P) was obtained from PDB. Molecular docking was conducted between selected compounds and EBOV NP. Clabistrin C was selected as a control. Complex of compounds EBOV NP and its amino acid residues were depicted by using Chimera X and LigPlot. Several potential compounds were selected for pharmacological activity prediction by PASS Online, toxicity analysis by ProTox-II, and drug likeness analysis with SWISSADME. Result showed that among the docked compound, hesperidin, cucurbitacin, ginsenoside RH2, and ginsenoside RO had lower binding energy compared to control. Moreover, all of those compounds had comparable hydrogen and hydrophobic interactions with EBOV NP. Further analysis showed it has potential biological function for Ebola disease, such as antiviral, antioxidant, and immunostimulant. All those compounds had low toxicity. As conclusion, there are four promising compounds that potentially inhibited the Ebolavirus proliferation

Acoplamiento molecular de potenciales inhibidores de Niemann Pick C1, involucrada en la transmisión del virus del Ébola

Abstract In this work, potential inhibitors of Ebola virus transmission were designed by analyzing the binding site of the Niemann Pick C1 protein, by means of molecular docking. For this investigation, a study of the binding site of the protein with cholesterol was carried out using the programs protein plus and Castp; Following this, the validation of the method was carried out using the Ligplot +, USCF Chimera software and AutoDockTools. Subsequently, molecules from other investigations were taken to study their interactions and based on this, new molecules were designed to which molecular coupling was applied to be able to choose the molecules with the best binding energies and finally a study was carried out on this selected group. Of the pharmacokinetic properties by means of Swiss ADME. Structures 18(a) and 22(b) presented the best results in the bioavailability radar, both present a high gastrointestinal absorption, comply with the Lipinski rules and their values ​​are within the established parameters, thus considering these molecules with great potential as inhibitors of the Ebola virus.Resumen En este trabajo se diseñaron potenciales inhibidores de la transmisión del virus del Ébola mediante el análisis del sitio de unión de la proteína Niemann Pick C1, por medio de acoplamiento molecular. Para esta investigación se hizo un estudio del sitio de unión de la proteína con el colesterol usando los programas protein plus y Castp; seguido a esto se realizó la validación del método utilizando los softwares Ligplot +, USCF Chimera y AutoDockTools. Posteriormente, se tomaron moléculas de otras investigaciones para estudiar sus interacciones y con base a esto se diseñaron nuevas moléculas a las cuales se les aplicó acoplamiento molecular para poder escoger las moléculas con mejores energías de unión y finalmente a este seleccionado grupo se les realizó un estudio de las propiedades farmacocinéticas por medio de Swiss ADME. Las estructuras 18 y 22 presentaron los mejores resultados en el radar de biodisponibilidad, ambas presentan una alta absorción gastrointestinal, cumplen con las reglas de Lipinski y sus valores están dentro de los parámetros establecidos, considerándose así estas moléculas con gran potencial como inhibidores del Virus del Èbola

Mushroom-derived bioactive compounds potentially serve as the inhibitors of SARS-CoV-2 main protease: An in silico approach

Background and aim Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become the world pandemic. There is a race to develop suitable drugs and vaccines for the disease. The anti-HIV protease drugs are currently repurposed for the potential treatment of COVID-19. The drugs were primarily screened against the SARS-CoV-2 main protease. With an urgent need for safe and effective drugs to treat the virus, we have explored natural products isolated from edible and medicinal mushrooms that have been reported to possess anti-HIV protease. Experimental procedures We have examined 36 compounds for their potential to be SARS-CoV-2 main protease inhibitors using molecular docking study. Moreover, drug-likeness properties including absorption, distribution, metabolism, excretion and toxicity were evaluated by in silico ADMET analysis. Results Our AutoDock study showed that 25 of 36 candidate compounds have the potential to inhibit the main viral protease based on their binding affinity against the enzyme’s active site when compared to the standard drugs. Interestingly, ADMET analysis and toxicity prediction revealed that 6 out of 25 compounds are the best drug-like property candidates, including colossolactone VIII, colossolactone E, colossolactone G, ergosterol, heliantriol F and velutin. Conclusion Our study highlights the potential of existing mushroom-derived natural compounds for further investigation and possibly can be used to fight against SARS-CoV-2 infection. Taxonomy (classification by evise) Disease, Infectious Disease, Respiratory System Disease, Covid-19, Traditional Medicine, Traditional Herbal Medicine, Phamaceutical Analysis

In Memory of Stefan Kunz

This issue of Viruses is a living memorial dedicated to Professor Stefan Kunz, who passed away too early in life, at 54. During his scientific career, Stefan made major contributions to the field of virology. He made seminal contributions to our understanding of how mammarenaviruses gain access to and are trafficked within their target cells. This issue of Viruses contains a collection of articles by leading researchers in different areas of virus–host cell interactions and who crossed pathways with Stefan. The topics covered in the issue include novel insights on mammeranavirus cell entry, host innate and adaptive immune responses to infection, recent developments on therapeutics against human pathogenic arenaviruses, as well as mammarenavirus ecology and molecular pathogenesis. The collection of articles is also a reflection of Stefan’s enthusiasm for exploring new ideas and his very collegial attitude reflected by his many collaborations, including the colleagues who have contributed sections to this memorial issue

Current Perspectives on Viral Disease Outbreaks

The COVID-19 pandemic has reminded the world that infectious diseases are still important. The last 40 years have experienced the emergence of new or resurging viral diseases such as AIDS, ebola, MERS, SARS, Zika, and others. These diseases display diverse epidemiologies ranging from sexual transmission to vector-borne transmission (or both, in the case of Zika). This book provides an overview of recent developments in the detection, monitoring, treatment, and control of several viral diseases that have caused recent epidemics or pandemics

Drug Repurposing

This book focuses on various aspects and applications of drug repurposing, the understanding of which is important for treating diseases. Due to the high costs and time associated with the new drug discovery process, the inclination toward drug repurposing is increasing for common as well as rare diseases. A major focus of this book is understanding the role of drug repurposing to develop drugs for infectious diseases, including antivirals, antibacterial and anticancer drugs, as well as immunotherapeutics

Structure-activity approaches for prediction of chemical reactivity and pharmacological properties of some heterocyclic compounds

Benzodiazepine drugs are widely prescribed to treat many psychiatric and neurologic disorders. As its pharmacological action is exerted in a sensitive area of the brain; ''the central nervous system'', it is crucial to provide detailed reports on the chemistry of benzodiazepines, model the mechanism of action that occurs with GABAA receptors, identify the overlap with other modulators, as well as explore the structural requirements that better potentiate the receptor response to benzodiazepines. This dissertation consists of two original studies that consider the new lines of research related to benzodiazepines, particularly the identification of three new TMD binding sites. The first study provides, on the one hand, an overview of the chemistry of six Benzodiazepine basic rings starting from structural characteristics, electronic properties, Global/local reactivities, up to intermolecular interactions with long-range nucleophilic/electrophilic reactants. This was achieved by combining a DFT investigation with a quantitative MEP analysis on the vdW surface. On the other hand, the performed molecular docking simulations allowed identifying the best binding modes, binding interactions, and binding affinities with residues, which helped to validate the quantitative MEP analysis predictions. The second study was conducted on a dataset of [3H]diazepam derivatives. First, molecular docking simulation was used to initially screen the dataset and select the best ligand/target complexes. Afterwise, the best-docked complexes were refined by performing molecular dynamics simulation for 1000 picoseconds. For both simulations, the binding modes, binding interactions, and binding affinities were thoroughly discussed and compared with each other and with outcomes collected from the literature. Additionally, the good pharmacokinetic properties (ADME prediction) as well as compliance with all druglikeness rules were checked via in silico tools for all the dataset compounds. Finally, a QSAR analysis was carried out using an improved version of PLS regression. Briefly, the dataset is randomly split into 10 000 training and test sets that involve, respectively, 80% and 20% of chemicals. Subsequently, 10 000 statistical simulations were conducted that; after excluding outlying observations, yielded 10 000 best training models following the Bayesian Information Criterion. Among these 10 000 best models, the best predictors with the highest probability of occurrence were selected. As a consequence, the derived PLS regression equation explains 63.2% of the variability in BDZ activity around its mean. Furthermore, Internal and external validation metrics assure the robustness and predictability of the developed model. The developed model was interpreted based on literature investigations and a combination of implemented approaches

The Development of a,b Unsaturated Sultam Probes for use in Chemical Biology

The field of chemical biology has become a powerful driving force among the continuing effort to elucidate medicinally relevant biological hot spots. These so called hot spots consist of reactive nucleophiles and electrophiles found along bio-pathways. Many nucleophilic amino acid residues, such as cysteine and serine, are known to react with a-b unsaturated electrophiles like Michael acceptors. In recent years systematic assays to uncover hot spot reactivity, including Activity Based Protein Profiling (ABPP), have risen to the forefront of chemical biology. However, these assays are dependent upon chemical probe molecules designed to interact with a given type of biological entity. Therefore, a persistent need exists for novel chemical probes with easily modifiable chemical, stereochemical, and electronic properties. Ideally these chemical properties are synthetically built into the probe in a rapid and combinatorial manner to yield a unique and easily modified probe molecule. This dissertation presents the design and synthesis of sultam chemical probes with a focus on a-b unsaturated systems. Chapter 1 contains a short review on a-b unsaturated Michael acceptors and biological reactivity, as well as the pharmaceutical history of enolic a-b unsaturated tetramic acids when combined with sultam molecules. Chapter 2 outlines the synthesis of six membered-triazole-fused sultams containing a-b unsaturated Michael acceptors. These chemical probes were generated via intermolecular click chemistry and ring closer by a novel C-vinylation reaction to form the sultam itself. Chapter 3 highlights the a-functionalization of tetramic acid inspired sultam probes or ‘sultamic acids,’ to generate endo-enol and exo-enamine-a-b unsaturated sultam probes. These probes will be given to collaborators for use in chemical biology assays