A COMPUTATIONAL DOCKING APPROACH AND ANTI-FUNGAL EFFECT OF AURANTOSIDE-G AND CLOTRIMAZOLE DRUG
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Candida albicans, a common fungus in the human mycobiota, can cause infections ranging from mild superficial to severe systemic candidiasis, leading to high death rates. The pathogenic potential of Candida albicans is influenced by the expression of proteins that play a crucial role in adhesion and invasion. This study aims to identify and target proteins responsible for the resistance of fungus to oxidative stress, a key factor in the ability of pathogens to evade phagocytic killing and survive in the host environment. The study utilized three-dimensional (3D) structures obtained from AlphaFold of the selected therapeutic targets. Furthermore, employing the various computational techniques, large-scale virtual screening against TIPdb, a phytochemical compounds database, domain analysis using InterPro, and molecular dynamics using DESMOND, identified top-scoring ligands binding with their respective proteins and their domains. Our study focused on key proteins, including HOG1, TSA1, TRX1, GPX3, SOD1, and YHB1, revealing their stability in molecular dynamics simulations and identifying them as potential targets for drug development. Conversely, proteins such as SSK1, SKN7, MPS1, CAP1, SOD2, CTA4, PRX1, CAT1, GRX3, and GPX1 displayed instability during simulations, suggesting susceptibility to inhibition by identified ligands. Furthermore, novel proteins (PRX1, SSK1, SKN7, CTA4, CAT1, GPX1, TSA1, TRX1, and GRX3) were identified as potential targets due to their unreported inhibition in existing literature and optimal binding affinity discovered through virtual screening. Nevertheless, further validation in preclinical studies is essential to advance targeted therapeutic strategies against Candida albicans infections.
With the expansion of immune-impaired people during second wave of Covid-19 the case of mucormycosis and aspergillosis caused by different fungi such as Rhizopus oryzae, Candida albicans and Aspergillus niger arose in different states. The current study reveals the molecular interaction of ligand and protein to find the novel and natural drug. The molecular docking was carried out by CB-dock tool and the ligand compound n-heptadecanol-1 were docked with different protein of opportunistic fungi. The most significant outcomes were depicted against C. albicans (−4.6 kcal/mol) followed by R. oryzae (−3.9 kcal/mol) and A. niger (−3.0 kcal/mol). n-heptadecanol-1 showed therapeutic potential and eliminates the issue of drug inadequacy that could act as potential anti-fungal agent.
In normal human microbiome, the polymorphic fungus Candida albicans is a crucial member. C. albicans resides mostly in individual as harmless commensal life. In specific situations, however, C. albicans can cause diseases that cause contaminations of the skin to life-threatening fundamental contaminations. Pathogenesis of Candida species is contributed by multiple factors. Some of the major contributors are enlisted here. These include host pathogen interaction, receptors molecule like TLR recognition, TLR signaling, C type lectin receptors, Dectin 1,2 and 3, mannose receptor, mincle, DC sign, Nod-Like Receptors (NLRs) and inflammasomes, soluble molecules in candida recognition, cellular responses to candida such as neutrophils, macrophages. This chapter enlightens all the components of candida pathogenicity by the assessment of Candida species pathogenic determinants. All together these will explain the current knowledge about how these determinant factors and receptors modulate virulence as well as consequent infection. Better understanding of candida pathogenicity mechanism can be the resultant of better treatment guidelines along with development of novel antifungal agents. Overall, in this review we present an update in the current understanding of the insight of pathogenicity mechanisms in this important human pathogen.
Candida albicans is a common commensal fungus that colonizes the oropharyngeal cavity, gastrointestinal and vaginal tract, and healthy individuals’ skin. In 50% of the population, C. albicans is part of the normal flora of the microbiota. The various clinical manifestations of Candida species range from localized, superficial mucocutaneous disorders to invasive diseases that involve multiple organ systems and are life-threatening. From systemic and local to hereditary and environmental, diverse factors lead to disturbances in Candida’s normal homeostasis, resulting in a transition from normal flora to pathogenic and opportunistic infections. The transition in the pathophysiology of the onset and progression of infection is also influenced by Candida’s virulence traits that lead to the development of candidiasis. Oral candidiasis has a wide range of clinical manifestations, divided into primary and secondary candidiasis. The main supply of C. albicans in the body is located in the gastrointestinal tract, and the development of infections occurs due to dysbiosis of the residential microbiota, immune dysfunction, and damage to the muco-intestinal barrier. The presence of C. albicans in the blood is associated with candidemia–invasive Candida infections. The commensal relationship exists as long as there is a balance between the host immune system and the virulence factors of C. albicans. This paper presents the virulence traits of Candida albicans and clinical manifestations of specific candidiasis.
Background
Conventional brackets are often used during orthodontic therapy of patients with malocclusion. The complex construction of such brackets greatly inhibits oral hygiene, which predisposes to increased carriage of microbiota. Orthodontic brackets could act as reservoir of yeast and predispose to oral candidosis. The aim of this study was to assess Candida prevalence and the role of oral hygiene during fixed appliance therapy . A further aim was to characterize the isolated yeasts according to their ability to form biofilms.
Methods
Seventeen participants (average age 17 ± 7 years) were monitored by taking oral rinses and elastomeric ligature samples, and by evaluating the approximal plaque index (API) and gingival bleeding index (GBI) before and after placement of the orthodontic conventional brackets for 12 weeks. Isolated yeasts were counted and biofilm formation was evaluated.
Results
One hundred and sixteen samples (67 oral rinses and 49 orthodontic elastomers) were collected. Ten patients (58.8% subjects) were Candida- carriers (two were colonized after bracket placement) and C. albicans was the most common species. The average number of yeasts in the oral cavity showed some fluctuation during the study, but in general had an upward trend (adj. R2 = 0.7967, p = 0.07025). A correlation was found between median number of yeasts and the periodontal indices (API, GBI). The average API values decreased in the Candida -carriers (adj. R ² = 0.95; p = 0.01709), while average GBI values increased in the noncarriers (adj. R ² = 0.92; p = 0.0256).
Conclusions
Treatment with orthodontic appliances promotes Candida yeast colonization, which is variable over time in terms of strain and species, with dominance of C. albicans , and without increased biofilm-forming activity. The API value decreases over time in carriers, and the GBI value increases in uncolonized patients, which may have predictive significance for the development of oral candidiasis during orthodontic treatment.
Based on benzoxazole and benzothiazole scaffold as an important pharmacophore, two series of 2-(aryloxymethyl) benzoxazole and benzothiazole derivatives were synthesized and their antifungal effects against eight phytopathogenic fungi were evaluated. Compounds 5a, 5b, 5h, and 5i exhibited significant antifungal activities against most of the pathogens tested. Especially 5a, 5b, 5h, 5i, 5j, and 6h inhibited the growth of F. solani with IC50 of 4.34–17.61 μg/mL, which were stronger than that of the positive control, hymexazol (IC50 of 38.92 μg/mL). 5h was the most potent inhibitor (IC50 of 4.34 μg/mL) against F. Solani, which was about nine times more potent than hymexazol. Most of the test compounds displayed significant antifungal effects against B. cinerea (IC50 of 19.92–77.41 μg/mL), among them, 5a was the best one (IC50 of 19.92 μg/mL). The structure-activity relationships (SARs) were compared and analyzed. The result indicates that the electron-drawing ability and position of the substituents have a significant impact on biological activities. Furthermore, docking studies were carried out on the lipid transfer protein sec14p from S. cerevisiae, and preliminarily verified the antifungal activities. Taken together, these results provide 2-(phenoxymethyl)benzo[d]oxazole as an encouraging framework that could lead to the development of potent novel antifungal agents.
Background:
PubChem is an open archive consisting of a set of three primary public databases (BioAssay, Compound, and Substance). It contains information on a broad range of chemical entities, including small molecules, lipids, carbohydrates, and (chemically modified) amino acid and nucleic acid sequences (including siRNA and miRNA). Currently (as of Nov. 2015), PubChem contains more than 150 million depositor-provided chemical substance descriptions, 60 million unique chemical structures, and 225 million biological activity test results provided from over 1 million biological assay records.
Description:
Many PubChem records (substances, compounds, and assays) include depositor-provided cross-references to scientific articles in PubMed. Some PubChem contributors provide bioactivity data extracted from scientific articles. Literature-derived bioactivity data complement high-throughput screening (HTS) data from the concluded NIH Molecular Libraries Program and other HTS projects. Some journals provide PubChem with information on chemicals that appear in their newly published articles, enabling concurrent publication of scientific articles in journals and associated data in public databases. In addition, PubChem links records to PubMed articles indexed with the Medical Subject Heading (MeSH) controlled vocabulary thesaurus.
Conclusion:
Literature information, both provided by depositors and derived from MeSH annotations, can be accessed using PubChem's web interfaces, enabling users to explore information available in literature related to PubChem records beyond typical web search results.
Graphical abstract:
Graphical abstractLiterature information for PubChem records is derived from various sources.
Herein, we report the synthesis, and characterization of a new series of 1,3,4-oxadiazole and 1,2,4-triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1H NMR, 13C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b, 6d, and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 μg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 μg/mL respectively. Particularly, the prepared scaffolds 8c, 8d, and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 μg/mL against A. flavus and 6d, 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 μg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H37Rv with MICs 3.26, and 6.48 μg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H-bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.Communicated by Ramaswamy H. Sarma.
Background:
Invasive fungal infections (IFIs) are primarily caused by Candida spp., Cryptococcus neoformans, Aspergillus spp., Mucor spp., Sporothrix spp., and Pneumocystis spp., which attack human organs with a strong pathogenicity and exhibit drug resistance against commonly used chemical drugs. Therefore, the search for alternative drugs with high efficacy, low resistance rates, few side effects, and synergistic antifungal effects remains a major challenge. The characteristics of natural products with structural and bioactive diversity, lower drug resistance, and rich resources make them a major focus of the development of antifungal drugs.
Objective:
This review attempts to summarize the origin, structure, and antifungal activity of natural products and their derivatives with MIC ≤ 20 µg/mL or 100 µM, focusing on their MoA and SAR.
Methods:
All pertinent literature databases were searched. The search keywords were antifungal or antifungals, terpenoids, steroidal saponins, alkaloid, phenols, lignans, flavonoids, quinones, macrolide, peptide, tetramic acid glycoside, polyene, polyketide, bithiazole, natural product, and derivatives. All the related literature (covering the past 20 years, 2001-2022) was evaluated.
Results:
In total, 340 natural products and 34 synthesized derivatives with antifungal activity from 301 studies were included in this review. These compounds were derived from terrestrial plants, ocean life, and microorganisms and exhibited in vitro and in vivo potent antifungal activity alone or in combination. The MoA and SARs of reported compounds were summarized whenever applicable.
Conclusion:
In this review, we attempted to review the available literature on natural antifungal products and their derivatives. Most of the studied compounds showed potent activity against Candida species, Aspergillus species, or Cryptococcus species. Some of the studied compounds also demonstrated the ability to impair the cell membrane and cell wall, inhibit hypha and biofilms, and cause mitochondrial dysfunction. Although the MoAs of these compounds are not well understood yet, they can be used as lead components for the development of new, effective, and safe antifungal agents through their novel mechanisms.
This book constitutes the Proceedings of the conference 'Chemical Structures: The International Language of Chemistry' which was held at Leeuwenhorst Congress Centre, Noordwijkerhout in the Netherlands, between May 31 and June 4, 1987. The conference was jointly sponsored by the Chemical Structure Association, the American Chemical Society Division of Chemical Information, and the Chemical Information Groups of the Royal Society of Chemistry and the German Chemical Society. The purpose of the conference was to bring together experts and an international professional audience to discuss and to further basic and applied research and development in the processing, storage, retrieval and use of chemical structures, to focus international attention on the importance of chemical information and the vital research being carried out in chemical information science and to foster co-operation among major chemical information organisations in North America and Europe. Subjects covered included integrated in-house databases, substructure searching methodology, spectral databanks, new technologies (microcomputers, CD-ROM, parallel processing and expert systems) and chemical reactions. The keynote address was given by Mike Lynch of the University of Sheffield. In this, the opening chapter of the book, Mike discusses progress made in chemical information science in the last fifteen years and describes his own approach to research. In a plenary session, Myra Williams of Merck, Sharp and Dohme considered future trends from the point of view of the information manager and strategic planner in industry. She emphasises the need for integration, open architecture and a uniform user interface.