Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease.
TL;DR: In vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid in the context of anti-dengue drug discovery.
Abstract: Dengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacologically bioactive compounds and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in vitro assay. From in silico analysis of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz. Ganodermanontriol (−6.291 kcal/mol), Lucidumol A (−5.993 kcal/mol), Ganoderic acid C2 (−5.948 kcal/mol) and Ganosporeric acid A (−5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to reference inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (−5.377 kcal/mol). These results were further studied for binding affinity and stability using the molecular mechanics/generalized Born surface area method and Molecular Dynamics simulations, respectively. Also, in vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.
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01 Jan 2009
TL;DR: The aim of the research presented in this thesis is to create new methods for design for manufacturing, by using several approaches of KE, and find the beneficial and less beneficial aspects of these methods in comparison to each other and earlier research.
Abstract: As companies strive to develop artefacts intended for services instead of traditional sell-off, new challenges in the product development process arise to promote continuous improvement and increasing market profits. This creates a focus on product life-cycle components as companies then make life-cycle commitments, where they are responsible for the function availability during the extent of the life-cycle, i.e. functional products. One of these life-cycle components is manufacturing; therefore, companies search for new approaches of success during manufacturability evaluation already in engineering design. Efforts have been done to support early engineering design, as this phase sets constraints and opportunities for manufacturing. These efforts have turned into design for manufacturing methods and guidelines. A further step to improve the life-cycle focus during early engineering design is to reuse results and use experience from earlier projects. However, because results and experiences created during project work are often not documented for reuse, only remembered by some people, there is a need for design support. Knowledge engineering (KE) is a methodology for creating knowledge-based systems, e.g. systems that enable reuse of earlier results and make available both explicit and tacit corporate knowledge, enabling the automated generation and evaluation of new engineering design solutions during early product development. There are a variety of KE-approaches, such as knowledge-based engineering, case-based reasoning and programming, which have been used in research to develop design for manufacturing methods and applications. There are, however, opportunities for research where several approaches and their interdependencies, to create a transparent picture of how KE can be used to support engineering design, are investigated. The aim of the research presented in this thesis is to create new methods for design for manufacturing, by using several approaches of KE, and find the beneficial and less beneficial aspects of these methods in comparison to each other and earlier research. This thesis presents methods and applications for design for manufacturing using KE. KE has been employed in several ways, namely rule-based, rule-, programmingand finite element analysis (FEA)-based, and ruleand plan-based, which are tested and compared with each other. Results show that KE can be used to generate information about manufacturing in several ways. The rule-based way is suitable for supporting life-cycle commitments, as engineering design and manufacturing can be integrated with maintenance and performance predictions during early engineering design, though limited to the firing of production rules. The rule-, programmingand FEA-based way can be used to integrate computer-aided design tools and virtual manufacturing for non-linear stress and displacement analysis. This way may also bridge the gap between engineering designers and computational experts, even though this way requires a larger effort to program than the rule-based. The ruleand planbased way can enable design for manufacturing in two fashions – based on earlier manufacturing plans and based on rules. Because earlier manufacturing plans, together with programming algorithms, can handle knowledge that may be more intricate to capture as rules, as opposed to the time demanding routine work that is often automated by means of rules, several opportunities for designing for manufacturing exist.
727 citations
TL;DR: It is proposed that a multi-faceted anti-inflammatory strategy based on pharmacological activation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), can be deployed against the virus.
141 citations
Cites background from "Discovery of Ganoderma lucidum trit..."
...Bardoxolone methyl (CDDO-Me), a semisynthetic pentacyclic triterpenoid, has been shown to possess a broad-spectrum anti-inflammatory activity against both DENV and Zika virus (ZIKV) [92]....
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...In addition, upregulation of the NRF2-transcriptional target heme oxygenase 1 (HO-1, gene name HMOX1) has been linked to an antiviral response against many viruses including HIV, hepatitis C virus (HCV), hepatitis B virus (HBV), enterovirus 71 (E71), influenza virus, respiratory syncytial virus (RSV), Dengue virus (DENV), and Ebola virus (EBOV) [57]....
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...Some triterpenoids isolated from Ganoderma lucidum have been found to be potential inhibitors of the NS2B-NS3 protease of DENV [89]....
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TL;DR: Combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic by selecting doxycycline and minocycline as potent inhibitor against SARS-CoV-2 Mpro which can used in combinational therapy against Sars-Cov-2 infection.
60 citations
TL;DR: The present study demonstrated that the low molecular weight subfractions III exhibited the strongest inhibitory activity towards breast carcinoma cells MDA-MB-231, prostatic carcinomas cells PC3, and breast cancer cells MCF7 with the half-maximal inhibitory concentration (IC50) value of 52,25 μg/mL.
Abstract: The aim of this study is to investigate in vitro the anticancer, antioxidant, and antibacterial activities of three low molecular weight subfractions I, II and III isolated from secondary metabolites produced by the wood degrading fungus Cerrena unicolor. The present study demonstrated that the low molecular weight subfractions III exhibited the strongest inhibitory activity towards breast carcinoma cells MDA-MB-231, prostatic carcinoma cells PC3, and breast cancer cells MCF7 with the half-maximal inhibitory concentration (IC50) value of 52,25 μg/mL, 60,66 μg/mL, and 54,92 μg/mL, respectively. The highest percentage of inhibition was noted at a concentration of 300 μg/mL in all the examined tumor lines. A significant percentage (59.08%) of ex-LMSIII inhibition of the MDA-MB-231 tumor line was reached at a concentration of 15 μg/ml, while the concentration applied did not affect normal human fibroblast cells. The low molecular weight subfraction III was the most effective and additionally showed the highest free radical 1,1-diphenyl-2-picryl-hydrazyl scavenging activity (IC50 20.39 μg/mL) followed by the low molecular weight subfraction I (IC50 64.14 μg/mL) and II (IC50 49.22 μg/mL). The antibacterial activity of the tested preparations was evaluated against three microorganisms: Bacillus subtilis, Staphylococcus aureus, and Escherichia coli. The MIC minimal inhibitory concentration (MIC) values for the low molecular weight subfraction I, II, and III showed a stronger inhibition effect on S. aureus than on B. subtilis and E. coli cells. The MIC values for the low molecular weight subfraction II against S. aureus, B. subtilis, and E. coli were 6.25, 12.5, and 100 mg/mL, respectively.
55 citations
TL;DR: Comparison molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 Mpro revealed R428, Teniposide, and Setileuton with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against Sars-Cov-2 infection.
Abstract: Recent outbreak of COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has raised serious global concern for public health. The viral main 3-chymotrypsin-like c...
40 citations
Cites methods or result from "Discovery of Ganoderma lucidum trit..."
...…MD trajectory for each docked complex were scrutinized in terms of last snapshot of simulated docked complex, root mean square deviation (RMSD), root mean square-fluctuations (RMSF), and protein-ligand contacts mapping with respect to 100 ns interval, as reported earlier ( Bharadwaj et al., 2019)....
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...Similar results for the energy components DGBind Coulomb and DGBind vdW contributing in the docked complexes were reported earlier ( Bharadwaj et al., 2019)....
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References
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TL;DR: Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
Abstract: A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.
4,666 citations
TL;DR: This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012, and the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide.
Abstract: This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over t...
4,337 citations
TL;DR: A complete set of intermolecular potential functions has been developed for use in computer simulations of proteins in their native environment and they have been parametrized directly to reproduce experimental thermodynamic and structural data on fluids.
Abstract: A complete set of intermolecular potential functions has been developed for use in computer simulations of proteins in their native environment. Parameters are reported for 25 peptide residues as well as the common neutral and charged terminal groups. The potential functions have the simple Coulomb plus Lennard-Jones form and are compatible with the widely used models for water, TIP4P, TIP3P, and SPC. The parameters were obtained and tested primarily in conjunction with Monte Carlo statistical mechanics simulations of 36 pure organic liquids and numerous aqueous solutions of organic ions representative of subunits in the side chains and backbones of proteins. Bond stretch, angle bend, and torsional terms have been adopted from the AMBER united-atom force field. As reported here, further testing has involved studies of conformational energy surfaces and optimizations of the crystal structures for four cyclic hexapeptides and a cyclic pentapeptide. The average root-mean-square deviation from the X-ray structures of the crystals is only 0.17 A for the atomic positions and 3% for the unit cell volumes. A more critical test was then provided by performing energy minimizations for the complete crystal of the protein crambin, including 182 water molecules that were initially placed via a Monte Carlo simulation. The resultant root-mean-square deviation for the non-hydrogen atoms is still ca. 0.2 A and the variation in the errors for charged, polar, and nonpolar residues is small. Improvement is apparent over the AMBER united-atom force field which has previously been demonstrated to be superior to many alternatives. Computer simulations are undoubtedly destined to became an increasingly important means for investigating the structures and dynamics of biomolecular systems.' At the heart of such theoretical calculations are the force fields that describe the interatomic interactions and the mechanics of deformations of the molecules.* There is also little doubt that there will be a continual evolution in force fields with added complexity and improved performance paralleling the availability of computer resources. Our own efforts in this area over the last few years have resulted in the OPLS potential functions for proteins whose development and performance are summarized here. These potential functions have a simple form and they have been parametrized directly to reproduce experimental thermodynamic and structural data on fluids. Consequently, they are computationally efficient and their description of proteins in solution or crystalline environments should be superior to many alterantives that have been developed with limited condensed-phase data. The latter point is pursued here primarily through calculations on the crystal structures for four cyclic hexapeptides, a cyclic pentapeptide, and the protein crambin. Improvements are apparent in comparison to the AMBER united-atom force field3 which has previously been shown to be superior to many alternative^.^ (1) Beveridge, D. L., Jorgensen, W. L., Eds. Ann. N.Y. Acad. Sci. 1986, 482. ( 2 ) For reviews, see: (a) Levitt, M. Annu. Reu. Biophys. Eioeng. 1982, 11, 251. (b) McCammon, J. A. Rep. Prog. Phys. 1984, 47, 1. (3) Weiner, S. J.; Kollman, P. A.; Case, D. A,; Singh, U. C.; Ghio, C.; Alagona, G.; Profeta, S.; Weiner, P. J. Am. Chem. SOC. 1984, 106, 765. Parametrization The peptide residues of proteins contain readily identifiable organic subunits such as amides, hydrocarbons, alcohols, thioethers, etc. In view of this and since data are available on the corresponding pure organic liquids, our approach to developing a force field for proteins was to build it up from parameters demonstrated to yield good descriptions of organic liquids. U1timately, the force field would need to treat both intramolecular terms for bond stretches, angle bends, and torsions, as well as the intermolecular and intramolecular nonbonded interactions. The latter are generally accepted to be the most difficult part of the problem and have been our focus.3 A simple, computationally efficient form was chosen to represent the nonbonded interactions through Coulomb and Lennard-Jones terms interacting between sites centered on nuclei (eq 1). Thus, the intermolecular inter-
4,328 citations
TL;DR: An overview of the PubChem Substance and Compound databases is provided, including data sources and contents, data organization, data submission using PubChem Upload, chemical structure standardization, web-based interfaces for textual and non-textual searches, and programmatic access.
Abstract: PubChem (https://pubchem.ncbi.nlm.nih.gov) is a public repository for information on chemical substances and their biological activities, launched in 2004 as a component of the Molecular Libraries Roadmap Initiatives of the US National Institutes of Health (NIH). For the past 11 years, PubChem has grown to a sizable system, serving as a chemical information resource for the scientific research community. PubChem consists of three inter-linked databases, Substance, Compound and BioAssay. The Substance database contains chemical information deposited by individual data contributors to PubChem, and the Compound database stores unique chemical structures extracted from the Substance database. Biological activity data of chemical substances tested in assay experiments are contained in the BioAssay database. This paper provides an overview of the PubChem Substance and Compound databases, including data sources and contents, data organization, data submission using PubChem Upload, chemical structure standardization, web-based interfaces for textual and non-textual searches, and programmatic access. It also gives a brief description of PubChem3D, a resource derived from theoretical three-dimensional structures of compounds in PubChem, as well as PubChemRDF, Resource Description Framework (RDF)-formatted PubChem data for data sharing, analysis and integration with information contained in other databases.
3,328 citations
TL;DR: Key concepts and specific features of small-molecule–protein docking methods are reviewed, selected applications are highlighted and recent advances that aim to address the acknowledged limitations of established approaches are discussed.
Abstract: Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes Here, we review key concepts and specific features of small-molecule-protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches
2,853 citations