Integrated structure model-based virtual screening approaches identified anti-cancer agents against prostate cancer by targeting MAOB protein

Abstract Background Flavin monoamine oxidase gene encodes a protein (MAOB) that forms a part of the flavin monoamine oxidase family in the outer membrane of mitochondria. It plays a role in the tissue metabolism of neuroactive and vasoactive amines as well as the oxidative deamination of xenobiotic and biogenic amines. However, overexpression of the receptor reduced apoptosis in cells, resulting in the progress of prostate sarcoma. Therefore, various kinds of MAOB antagonists are often used to fix an apoptosis mechanism that makes it hard to get rid of cancer from live tissues. Moreover, chemical compounds that have been discovered to be MAOB inhibitors to date exhibit side effects that are causing problems in chemotherapy treatment. The study aims to discover new purchasable compound that induces apoptosis by allowing caspases to operate at their maximum efficiency and is low toxic. Methods With the assistance of virtual screening, molecular docking, and molecular dynamics simulation (MD), a structure-based pharmacophore model of the protein active site cavity was made. Twenty hits were found, and then a molecular docking strategy was used to choose four molecules to study in more depth. MD simulations were used to check the stability of the four compounds, and they were all shown to be stable when bound to the target protein. Results Four newly discovered compounds, included with ZINC ID Such as ZINC12143050, ZINC08301324, ZINC16743012, and ZINC64165826 with binding scores of − 11.7, − 11.4, − 11.2 and − 11.1 kcal/mol, respectively, may serve as lead compounds for the treatment of prostate cancer associated with MAOB; however, further evaluation through wet lab is needed to determine the compounds effectiveness. Conclusion A structure-based model was initially developed, followed by molecular docking, ADMET analysis, and MD simulation. The top four natural compounds identified in the A-to-Z virtual screening process could serve as lead molecules in the fight against prostate cancer

Antifungal Activity of Human Cathelicidin LL-37, a Membrane Disrupting Peptide, by Triggering Oxidative Stress and Cell Cycle Arrest in <i>Candida auris</i>

Candida auris, an evolving multidrug-resistant pathogenic yeast, is known for causing severe invasive infections associated with high mortality rates in hospitalized individuals. Distinct from other Candida species, C. auris can persist for longer periods on different surfaces and is resistant to all of the major classes of antifungal drugs. Therefore, there is an urgent need for new antimycotic drugs with improved efficacy and reduced toxicity. The development of new antifungals based on antimicrobial peptides from various sources is considered a promising alternative. In this study, we examined the in vitro anti-yeast activity of the human cathelicidin peptides LL-37 against clinical strains of C. auris alone and in combination with different antifungal drugs by broth microdilution assay. To understand the antifungal mechanism of action, cell envelopes, cell cycle arrest, and effect on oxidative stress enzymes were studied using standard protocols. The minimum inhibitory and fungicidal concentrations of cathelicidin LL-37 ranged from 25–100 and 50–200 µg/mL, respectively. A combination interaction in a 1:1 ratio (cathelicidin LL-37: antifungal drug) resulted in 70% synergy with fluconazole and 100% synergy with amphotericin B and caspofungin. Assessment of the C. auris membrane by using propidium iodide assay after exposure to cathelicidin LL-37 linked membrane permeabilization with inhibition of C. auris cell growth and viability. These results were backed up by scanning electron microscopy studies demonstrating that exposure with cathelicidin LL-37 caused C. auris cells to undergo extensive surface changes. Spectrophotometric analysis revealed that cathelicidin LL-37 caused oxidative stress in C. auris, as is evident from the significant increase in the activity of primary antioxidant enzymes. In addition, cathelicidin LL-37 inhibited the cell cycle and accumulated cells in the S phase. Therefore, these results specify the potential of cathelicidin LL-37 for developing a new and effective anti-Candida agent

Preliminary studies on ligand-based design and evaluation of new mycobacterial ATP synthase inhibitors

Background: Tuberculosis is a threat to humankind due to the development of resistance against the existing drugs, so new drugs are an absolute necessity. Neuroleptic phenothiazines were reported for antitubercular activity, but the associated antipsychotic effect restricted their antitubercular use. Objective: Novel mycobacterial ATP synthase inhibitors having structural similarity with phenothiazines were designed in an attempt to develop potent antitubercular agents with no or less side effects. Methods: The designed molecules were synthesized and screened against Mycobacterium tuberculosis H37Rv (Mtb). The compounds with strongest growth inhibition of whole Mtb (S3, S4, S9, S10, and S16) were screened for ATP synthesis inhibition using inverted membrane vesicles from Mycobacterium smegmatis, and were also screened for blood-brain barrier (BBB) permeability and mammalian cell cytotoxicity to assess the possible side effects. Results: Among all the compounds, S9 and S10 were found to be the most active (6.25 µg/mL) against Mtb and were comparable to chlorpromazine (12.5 µg/mL). Moreover, the compounds inhibited ATP synthesis at IC50 of 14 and 10.4 µM, respectively. A better correlation between MIC and IC50 observed, indicated that the compounds acted through mycobacterial ATP synthase inhibition. The blood-brain barrier (BBB) crossing ability of the compounds (S9, S10) was found to be less, indicating diminished CNS side effects. The compounds (S3, S4, S9, S10, and S16) were also marked safe against mammalian VERO cells, as CC50 was > 102 µg/mL. Conclusion: The enhanced antitubercular activity with reduced BBB permeability exhibited by the compounds has good prospect to develop them as antitubercular drugs

Enhanced Gravitational Search Optimization with Hybrid Deep Learning Model for COVID-19 Diagnosis on Epidemiology Data

Effective screening provides efficient and quick diagnoses of COVID-19 and could alleviate related problems in the health care system. A prediction model that combines multiple features to assess contamination risks was established in the hope of supporting healthcare workers worldwide in triaging patients, particularly in situations with limited health care resources. Furthermore, a lack of diagnosis kits and asymptomatic cases can lead to missed or delayed diagnoses, exposing visitors, medical staff, and patients to 2019-nCoV contamination. Non-clinical techniques including data mining, expert systems, machine learning, and other artificial intelligence technologies have a crucial role to play in containment and diagnosis in the COVID-19 outbreak. This study developed Enhanced Gravitational Search Optimization with a Hybrid Deep Learning Model (EGSO-HDLM) for COVID-19 diagnoses using epidemiology data. The major aim of designing the EGSO-HDLM model was the identification and classification of COVID-19 using epidemiology data. In order to examine the epidemiology data, the EGSO-HDLM model employed a hybrid convolutional neural network with a gated recurrent unit based fusion (HCNN-GRUF) model. In addition, the hyperparameter optimization of the HCNN-GRUF model was improved by the use of the EGSO algorithm, which was derived by including the concepts of cat map and the traditional GSO algorithm. The design of the EGSO algorithm helps in reducing the ergodic problem, avoiding premature convergence, and enhancing algorithm efficiency. To demonstrate the better performance of the EGSO-HDLM model, experimental validation on a benchmark dataset was performed. The simulation results ensured the enhanced performance of the EGSO-HDLM model over recent approaches

Cytochrome bd-I from Escherichia coli is catalytically active in the absence of the CydH subunit

Cytochrome bd-I from Escherichia coli is a terminal oxidase in the respiratory chain that plays an important role under stress conditions. Cytochrome bd-I was thought to consist of the major subunits CydA and CydB plus the small CydX subunit. Recent high-resolution structures of cytochrome bd-I demonstrated the presence of an additional subunit, CydH/CydY (called CydH here), the function of which is unclear. In this report, we show that in the absence of CydH, cytochrome bd-I is catalytically active, can sustain bacterial growth and displays haem spectra and susceptibility for haem-binding inhibitors comparable to the wild-type enzyme. Removal of CydH did not elicit catalase activity of cytochrome bd-I in our experimental system. Taken together, in the absence of the CydH subunit cytochrome bd-I retained key enzymatic properties

Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae

The development of resistance to carbapenems in Klebsiella pneumoniae due to the production of metallo-β-lactamases (MBLs) is a critical public health problem because carbapenems are the last-resort drugs used for treating severe infections of extended-spectrum β-lactamases (ESBLs) producing K. pneumoniae. Restoring the activity of carbapenems by the inhibition of metallo-β-lactamases is a valuable approach to combat carbapenem resistance. In this study, two well-characterized clinical multidrug and carbapenem-resistant K. pneumoniae isolates were used. The sub-inhibitory concentrations of pantoprazole and the well-reported metallo-β-lactamase inhibitor captopril inhibited the hydrolytic activities of metallo-β-lactamases, with pantoprazole having more inhibiting activities. Both drugs, when used in combination with meropenem, exhibited synergistic activities. Pantoprazole could also downregulate the expression of the metallo-β-lactamase genes blaNDM and blaVIM. A docking study revealed that pantoprazole could bind to and chelate zinc ions of New Delhi and Verona integron-encoded MBL (VIM) enzymes with higher affinity than the control drug captopril and with comparable affinity to the natural ligand meropenem, indicating the significant inhibitory activity of pantoprazole against metallo-β-lactamases. In conclusion, pantoprazole can be used in combination with meropenem as a new strategy for treating serious infections caused by metallo-β-lactamases producing K. pneumoniae

Cardiolipin enhances the enzymatic activity of cytochrome bd and cytochrome bo ₃ solubilized in dodecyl-maltoside

Cardiolipin (CL) is a lipid that is found in the membranes of bacteria and the inner membranes of mitochondria. CL can increase the activity of integral membrane proteins, in particular components of respiratory pathways. We here report that CL activated detergent-solubilized cytochrome bd, a terminal oxidase from Escherichia coli. CL enhanced the oxygen consumption activity ~ twofold and decreased the apparent KM value for ubiquinol-1 as substrate from 95 µM to 35 µM. Activation by CL was also observed for cytochrome bd from two Gram-positive species, Geobacillus thermodenitrificans and Corynebacterium glutamicum, and for cytochrome bo3 from E. coli. Taken together, CL can enhance the activity of detergent-solubilized cytochrome bd and cytochrome bo3.</p

Stachybotrys chartarum&mdash;A Hidden Treasure: Secondary Metabolites, Bioactivities, and Biotechnological Relevance

Fungi are renowned as a fountainhead of bio-metabolites that could be employed for producing novel therapeutic agents, as well as enzymes with wide biotechnological and industrial applications. Stachybotrys chartarum (black mold) (Stachybotriaceae) is a toxigenic fungus that is commonly found in damp environments. This fungus has the capacity to produce various classes of bio-metabolites with unrivaled structural features, including cyclosporins, cochlioquinones, atranones, trichothecenes, dolabellanes, phenylspirodrimanes, xanthones, and isoindoline and chromene derivatives. Moreover, it is a source of various enzymes that could have variable biotechnological and industrial relevance. The current review highlights the formerly published data on S. chartarum, including its metabolites and their bioactivities, as well as industrial and biotechnological relevance dated from 1973 to the beginning of 2022. In this work, 215 metabolites have been listed and 138 references have been cited

Comparative Analysis of the Impact of Urolithins on the Composition of the Gut Microbiota in Normal-Diet Fed Rats

The gut microbiota consists of a community of microorganisms that inhabit the large intestine. These microbes play important roles in maintaining gut barrier integrity, inflammation, lipid and carbohydrate metabolism, immunity, and protection against pathogens. However, recent studies have shown that dysfunction in the gut microbiota composition can lead to the development of several diseases. Urolithin A has recently been approved as a functional food ingredient. In this study, we examined the potentials of urolithin A (Uro-A) and B (Uro-B) in improving metabolic functions and their impact on gut microbiota composition under a metabolically unchallenged state in normal rats. Male Wistar rats (n = 18) were randomly segregated into three groups, with Group 1 serving as the control group. Groups 2 and 3 were administered with 2.5 mg/kg Uro-A and Uro-B, respectively, for four weeks. Our results showed that both Uro-A and B improved liver and kidney functions without affecting body weight. Metagenomic analysis revealed that both Uro-A and B induced the growth of Akkermansia. However, Uro-A decreased species diversity and microbial richness and negatively impacted the composition of pathogenic microbes in normal rats. Taken together, this study showed the differential impacts of Uro-A and B on the gut microbiota composition in normal rats and would thus serve as a guide in the choice of these metabolites as a functional food ingredient or prebiotic

Application of Mathematical Modeling and Computational Tools in the Modern Drug Design and Development Process

The conventional drug discovery approach is an expensive and time-consuming process, but its limitations have been overcome with the help of mathematical modeling and computational drug design approaches. Previously, finding a small molecular candidate as a drug against a disease was very costly and required a long time to screen a compound against a specific target. The development of novel targets and small molecular candidates against different diseases including emerging and reemerging diseases remains a major concern and necessitates the development of novel therapeutic targets as well as drug candidates as early as possible. In this regard, computational and mathematical modeling approaches for drug development are advantageous due to their fastest predictive ability and cost-effectiveness features. Computer-aided drug design (CADD) techniques utilize different computer programs as well as mathematics formulas to comprehend the interaction of a target and drugs. Traditional methods to determine small-molecule candidates as a drug have several limitations, but CADD utilizes novel methods that require little time and accurately predict a compound against a specific disease with minimal cost. Therefore, this review aims to provide a brief insight into the mathematical modeling and computational approaches for identifying a novel target and small molecular candidates for curing a specific disease. The comprehensive review mainly focuses on biological target prediction, structure-based and ligand-based drug design methods, molecular docking, virtual screening, pharmacophore modeling, quantitative structure&ndash;activity relationship (QSAR) models, molecular dynamics simulation, and MM-GBSA/MM-PBSA approaches along with valuable database resources and tools for identifying novel targets and therapeutics against a disease. This review will help researchers in a way that may open the road for the development of effective drugs and preventative measures against a disease in the future as early as possible