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1.
Mar Drugs ; 20(3)2022 Mar 20.
Article in English | MEDLINE | ID: covidwho-1760762

ABSTRACT

The world is already facing the devastating effects of the SARS-CoV-2 pandemic. A disseminated mucormycosis epidemic emerged to worsen this situation, causing havoc, especially in India. This research aimed to perform a multitargeted docking study of marine-sponge-origin bioactive compounds against mucormycosis. Information on proven drug targets and marine sponge compounds was obtained via a literature search. A total of seven different targets were selected. Thirty-five compounds were chosen using the PASS online program. For homology modeling and molecular docking, FASTA sequences and 3D structures for protein targets were retrieved from NCBI and PDB databases. Autodock Vina in PyRx 0.8 was used for docking studies. Further, molecular dynamics simulations were performed using the IMODS server for top-ranked docked complexes. Moreover, the drug-like properties and toxicity analyses were performed using Lipinski parameters in Swiss-ADME, OSIRIS, ProTox-II, pkCSM, and StopTox servers. The results indicated that naamine D, latrunculin A and S, (+)-curcudiol, (+)-curcuphenol, aurantoside I, and hyrtimomine A had the highest binding affinity values of -8.8, -8.6, -9.8, -11.4, -8.0, -11.4, and -9.0 kcal/mol, respectively. In sum, all MNPs included in this study are good candidates against mucormycosis. (+)-curcudiol and (+)-curcuphenol are promising compounds due to their broad-spectrum target inhibition potential.


Subject(s)
Antifungal Agents , Biological Products , COVID-19/drug therapy , Mucormycosis/drug therapy , Porifera/chemistry , SARS-CoV-2 , Animals , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacokinetics , Antifungal Agents/toxicity , Biological Products/chemistry , Biological Products/isolation & purification , Biological Products/pharmacokinetics , Biological Products/toxicity , COVID-19/complications , Coinfection , Fungal Proteins/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Mucormycosis/etiology , Toxicity Tests, Acute
2.
Brief Bioinform ; 23(2)2022 03 10.
Article in English | MEDLINE | ID: covidwho-1684526

ABSTRACT

The application of machine intelligence in biological sciences has led to the development of several automated tools, thus enabling rapid drug discovery. Adding to this development is the ongoing COVID-19 pandemic, due to which researchers working in the field of artificial intelligence have acquired an active interest in finding machine learning-guided solutions for diseases like mucormycosis, which has emerged as an important post-COVID-19 fungal complication, especially in immunocompromised patients. On these lines, we have proposed a temporal convolutional network-based binary classification approach to discover new antifungal molecules in the proteome of plants and animals to accelerate the development of antifungal medications. Although these biomolecules, known as antifungal peptides (AFPs), are part of an organism's intrinsic host defense mechanism, their identification and discovery by traditional biochemical procedures is arduous. Also, the absence of a large dataset on AFPs is also a considerable impediment in building a robust automated classifier. To this end, we have employed the transfer learning technique to pre-train our model on antibacterial peptides. Subsequently, we have built a classifier that predicts AFPs with accuracy and precision of 94%. Our classifier outperforms several state-of-the-art models by a considerable margin. The results of its performance were proven as statistically significant using the Kruskal-Wallis H test, followed by a post hoc analysis performed using the Tukey honestly significant difference (HSD) test. Furthermore, we identified potent AFPs in representative animal (Histatin) and plant (Snakin) proteins using our model. We also built and deployed a web app that is freely available at https://tcn-afppred.anvil.app/ for the identification of AFPs in protein sequences.


Subject(s)
Antifungal Agents/chemistry , Deep Learning , Drug Discovery/methods , Neural Networks, Computer , Algorithms , Antifungal Agents/pharmacology , Artificial Intelligence , Databases, Factual , Humans , ROC Curve , Reproducibility of Results , Software , Workflow
3.
Int J Mol Sci ; 22(23)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542586

ABSTRACT

Compounds of natural origin, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovering new medicines. In this review, we summarize the naturally occurring ellagitannins, sanguiins, which are bioactive constituents of various traditional medicinal plants, especially from the Rosaceae family. In-depth studies of sanguiin H-6 as an antimicrobial, antiviral, anticancer, anti-inflammatory, and osteoclastogenesis inhibitory agent have led to potent drug candidates. In addition, recently, virtual screening studies have suggested that sanguiin H-6 might increase resistance toward SARS-CoV-2 in the early stages of infection. Further experimental investigations on ADMET (absorption, distribution, metabolism, excretion, and toxicity) supplemented with molecular docking and molecular dynamics simulation are still needed to fully understand sanguiins' mechanism of action. In sum, sanguiins appear to be promising compounds for additional studies, especially for their application in therapies for a multitude of common and debilitating ailments.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/pharmacology , Animals , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pharmacokinetics , Rosaceae/chemistry , SARS-CoV-2/drug effects
4.
Molecules ; 26(22)2021 Nov 20.
Article in English | MEDLINE | ID: covidwho-1524087

ABSTRACT

A series of methyl ß-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich's ascites carcinoma (EAC) cells with an IC50 value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.


Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Galactose/analogs & derivatives , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacokinetics , Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cell Line, Tumor , Coronavirus 3C Proteases/chemistry , Galactose/chemistry , Galactose/pharmacokinetics , Galactose/pharmacology , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/enzymology , Static Electricity , Thermodynamics
5.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1475773

ABSTRACT

Fungal infections or mycosis cause a wide range of diseases in humans and animals. The incidences of community acquired; nosocomial fungal infections have increased dramatically after the emergence of COVID-19 pandemic. The increase in number of patients with immunodeficiency / immunosuppression related diseases, resistance to existing antifungal compounds and availability of limited therapeutic options has triggered the search for alternative antifungal molecules. In this direction, antifungal peptides (AFPs) have received a lot of interest as an alternative to currently available antifungal drugs. Although the AFPs are produced by diverse population of living organisms, identifying effective AFPs from natural sources is time-consuming and expensive. Therefore, there is a need to develop a robust in silico model capable of identifying novel AFPs in protein sequences. In this paper, we propose Deep-AFPpred, a deep learning classifier that can identify AFPs in protein sequences. We developed Deep-AFPpred using the concept of transfer learning with 1DCNN-BiLSTM deep learning algorithm. The findings reveal that Deep-AFPpred beats other state-of-the-art AFP classifiers by a wide margin and achieved approximately 96% and 94% precision on validation and test data, respectively. Based on the proposed approach, an online prediction server is created and made publicly available at https://afppred.anvil.app/. Using this server, one can identify novel AFPs in protein sequences and the results are provided as a report that includes predicted peptides, their physicochemical properties and motifs. By utilizing this model, we identified AFPs in different proteins, which can be chemically synthesized in lab and experimentally validated for their antifungal activity.


Subject(s)
Antifungal Agents/chemistry , COVID-19 , Mucormycosis , Pandemics/prevention & control , Peptides/chemistry , SARS-CoV-2 , Antifungal Agents/therapeutic use , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/microbiology , Humans , Mucormycosis/drug therapy , Mucormycosis/epidemiology
6.
Molecules ; 26(6)2021 Mar 23.
Article in English | MEDLINE | ID: covidwho-1389468

ABSTRACT

Natural products are gaining more interest recently, much of which focuses on those derived from medicinal plants. The common chicory (Cichorium intybus L.), of the Astraceae family, is a prime example of this trend. It has been proven to be a feasible source of biologically relevant elements (K, Fe, Ca), vitamins (A, B1, B2, C) as well as bioactive compounds (inulin, sesquiterpene lactones, coumarin derivatives, cichoric acid, phenolic acids), which exert potent pro-health effects on the human organism. It displays choleretic and digestion-promoting, as well as appetite-increasing, anti-inflammatory and antibacterial action, all owing to its varied phytochemical composition. Hence, chicory is used most often to treat gastrointestinal disorders. Chicory was among the plants with potential against SARS-CoV-2, too. To this and other ends, roots, herb, flowers and leaves are used. Apart from its phytochemical applications, chicory is also used in gastronomy as a coffee substitute, food or drink additive. The aim of this paper is to present, in the light of the recent literature, the chemical composition and properties of chicory.


Subject(s)
Chicory/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Chicory/physiology , Cooking , Food Hypersensitivity/etiology , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Plants, Medicinal/chemistry
7.
Eur J Med Chem ; 224: 113696, 2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1300086

ABSTRACT

The antimicrobial resistance (AMR) is an intractable problem for the world. Metal ions are essential for the cell process and biological function in microorganisms. Many metal-based complexes with the potential for releasing ions are more likely to be absorbed for their higher lipid solubility. Hence, this review highlights the clinical potential of organometallic compounds for the treatment of infections caused by bacteria or fungi in recent five years. The common scaffolds, including antimicrobial peptides, N-heterocyclic carbenes, Schiff bases, photosensitive-grand-cycle skeleton structures, aliphatic amines-based ligands, and special metal-based complexes are summarized here. We also discuss their therapeutic targets and the risks that should be paid attention to in the future studies, aiming to provide information for researchers on metal-based complexes as antimicrobial agents and inspire the design and synthesis of new antimicrobial drugs.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Bacteria/drug effects , Drug Discovery , Fungi/drug effects , Organometallic Compounds/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Microbial Sensitivity Tests , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry
8.
Molecules ; 26(12)2021 Jun 10.
Article in English | MEDLINE | ID: covidwho-1282534

ABSTRACT

Multi-drug resistant pathogens are a rising danger for the future of mankind. Iodine (I2) is a centuries-old microbicide, but leads to skin discoloration, irritation, and uncontrolled iodine release. Plants rich in phytochemicals have a long history in basic health care. Aloe Vera Barbadensis Miller (AV) and Salvia officinalis L. (Sage) are effectively utilized against different ailments. Previously, we investigated the antimicrobial activities of smart triiodides and iodinated AV hybrids. In this work, we combined iodine with Sage extracts and pure AV gel with polyvinylpyrrolidone (PVP) as an encapsulating and stabilizing agent. Fourier transform infrared spectroscopy (FT-IR), Ultraviolet-visible spectroscopy (UV-Vis), Surface-Enhanced Raman Spectroscopy (SERS), microstructural analysis by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and X-Ray-Diffraction (XRD) analysis verified the composition of AV-PVP-Sage-I2. Antimicrobial properties were investigated by disc diffusion method against 10 reference microbial strains in comparison to gentamicin and nystatin. We impregnated surgical sutures with our biohybrid and tested their inhibitory effects. AV-PVP-Sage-I2 showed excellent to intermediate antimicrobial activity in discs and sutures. The iodine within the polymeric biomaterial AV-PVP-Sage-I2 and the synergistic action of the two plant extracts enhanced the microbial inhibition. Our compound has potential for use as an antifungal agent, disinfectant and coating material on sutures to prevent surgical site infections.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Aloe/chemistry , Antifungal Agents/chemistry , Gentamicins/chemistry , Microbial Sensitivity Tests , Microscopy, Electron, Scanning/methods , Nystatin/chemistry , Plant Extracts/chemistry , Povidone/chemistry , Salvia/chemistry , Salvia officinalis/chemistry , Spectrometry, X-Ray Emission/methods , Spectroscopy, Fourier Transform Infrared/methods , X-Ray Diffraction/methods
9.
Int J Mol Sci ; 22(9)2021 Apr 25.
Article in English | MEDLINE | ID: covidwho-1231493

ABSTRACT

Candida auris is a novel and major fungal pathogen that has triggered several outbreaks in the last decade. The few drugs available to treat fungal diseases, the fact that this yeast has a high rate of multidrug resistance and the occurrence of misleading identifications, and the ability of forming biofilms (naturally more resistant to drugs) has made treatments of C. auris infections highly difficult. This review intends to quickly illustrate the main issues in C. auris identification, available treatments and the associated mechanisms of resistance, and the novel and alternative treatment and drugs (natural and synthetic) that have been recently reported.


Subject(s)
Antifungal Agents/pharmacology , Candida/isolation & purification , Candidiasis/drug therapy , Drug Resistance, Fungal/drug effects , Antifungal Agents/chemistry , Antifungal Agents/therapeutic use , Azoles/pharmacology , Candida/drug effects , Candidiasis/microbiology , Drug Therapy, Combination , Echinocandins/pharmacology , Humans , Mycology/methods , Polyenes/pharmacology , Treatment Failure
10.
Molecules ; 25(22)2020 Nov 11.
Article in English | MEDLINE | ID: covidwho-917015

ABSTRACT

Flavonoids are phytochemical compounds present in many plants, fruits, vegetables, and leaves, with potential applications in medicinal chemistry. Flavonoids possess a number of medicinal benefits, including anticancer, antioxidant, anti-inflammatory, and antiviral properties. They also have neuroprotective and cardio-protective effects. These biological activities depend upon the type of flavonoid, its (possible) mode of action, and its bioavailability. These cost-effective medicinal components have significant biological activities, and their effectiveness has been proved for a variety of diseases. The most recent work is focused on their isolation, synthesis of their analogs, and their effects on human health using a variety of techniques and animal models. Thousands of flavonoids have been successfully isolated, and this number increases steadily. We have therefore made an effort to summarize the isolated flavonoids with useful activities in order to gain a better understanding of their effects on human health.


Subject(s)
Flavonoids/chemistry , Flavonoids/pharmacology , Alzheimer Disease/drug therapy , Alzheimer Disease/prevention & control , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cardiovascular System/drug effects , Flavonoids/economics , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Nervous System/drug effects , Neurons/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Plant Extracts/pharmacology , Plant Leaves/chemistry , Plants/chemistry , Polyphenols/chemistry , Polyphenols/pharmacology , Quercetin/chemistry , Quercetin/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stroke/drug therapy , Stroke/prevention & control
11.
J Med Chem ; 64(7): 3885-3896, 2021 04 08.
Article in English | MEDLINE | ID: covidwho-1155689

ABSTRACT

Quinacrine (QC) and chloroquine (CQ) have antimicrobial and antiviral activities as well as antimalarial activity, although the mechanisms remain unknown. QC increased the antimicrobial activity against yeast exponentially with a pH-dependent increase in the cationic amphiphilic drug (CAD) structure. CAD-QC localized in the yeast membranes and induced glucose starvation by noncompetitively inhibiting glucose uptake as antipsychotic chlorpromazine (CPZ) did. An exponential increase in antimicrobial activity with pH-dependent CAD formation was also observed for CQ, indicating that the CAD structure is crucial for its pharmacological activity. A decrease in CAD structure with a slight decrease in pH from 7.4 greatly reduced their effects; namely, these drugs would inefficiently act on falciparum malaria and COVID-19 pneumonia patients with acidosis, resulting in resistance. The decrease in CAD structure at physiological pH was not observed for quinine, primaquine, or mefloquine. Therefore, restoring the normal blood pH or using pH-insensitive quinoline drugs might be effective for these infectious diseases with acidosis.


Subject(s)
Antifungal Agents/pharmacology , Chloroquine/pharmacology , Quinacrine/pharmacology , Surface-Active Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Cell Membrane/metabolism , Chloroquine/chemistry , Chloroquine/metabolism , Hydrogen-Ion Concentration , Microbial Sensitivity Tests , Molecular Structure , Monosaccharide Transport Proteins/antagonists & inhibitors , Protons , Quinacrine/chemistry , Quinacrine/metabolism , Saccharomyces cerevisiae/drug effects , Surface-Active Agents/chemistry , Surface-Active Agents/metabolism
12.
Molecules ; 26(6)2021 Mar 23.
Article in English | MEDLINE | ID: covidwho-1154456

ABSTRACT

Bats are unique in their potential to serve as reservoir hosts for intracellular pathogens. Recently, the impact of COVID-19 has relegated bats from biomedical darkness to the frontline of public health as bats are the natural reservoir of many viruses, including SARS-Cov-2. Many bat genomes have been sequenced recently, and sequences coding for antimicrobial peptides are available in the public databases. Here we provide a structural analysis of genome-predicted bat cathelicidins as components of their innate immunity. A total of 32 unique protein sequences were retrieved from the NCBI database. Interestingly, some bat species contained more than one cathelicidin. We examined the conserved cysteines within the cathelin-like domain and the peptide portion of each sequence and revealed phylogenetic relationships and structural dissimilarities. The antibacterial, antifungal, and antiviral activity of peptides was examined using bioinformatic tools. The peptides were modeled and subjected to docking analysis with the region binding domain (RBD) region of the SARS-CoV-2 Spike protein. The appearance of multiple forms of cathelicidins verifies the complex microbial challenges encountered by these species. Learning more about antiviral defenses of bats and how they drive virus evolution will help scientists to investigate the function of antimicrobial peptides in these species.


Subject(s)
Cathelicidins/chemistry , Cathelicidins/pharmacology , Chiroptera/genetics , Spike Glycoprotein, Coronavirus/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antimicrobial Cationic Peptides/chemistry , Antimicrobial Cationic Peptides/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Binding Sites , Cathelicidins/genetics , Cathelicidins/metabolism , Computational Biology/methods , Computer Simulation , Genome , Molecular Docking Simulation , Phylogeny
13.
Molecules ; 26(2)2021 Jan 13.
Article in English | MEDLINE | ID: covidwho-1034745

ABSTRACT

Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule's tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a "taming" strategy), we found that by covalently attaching one or more facial amphiphiles ("floats") to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such "monomer control" and "taming" strategies to other membrane-disrupting antimicrobial agents is briefly discussed.


Subject(s)
Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Fungi/drug effects , Amphotericin B/chemistry , Antifungal Agents/chemistry , Humans , Microbial Sensitivity Tests , Molecular Conformation
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