Virtual Screening of Coffea arabica Phytochemicals as Natural β-Lactamase Inhibitors

Antioxidant activity, metabolic profiling, in-silico molecular docking and ADMET analysis of nano selenium treated sesame seed bioactive compounds as potential novel drug targets against cardiovascular disease related receptors

Design, synthesis, characterization, antimicrobial activity, cytotoxicity, molecular docking, and in-silico ADMET analysis of the novel cefuroxime derivatives

Aim: Cancer, characterized by uncontrolled cell growth, poses global health challenges, while natural bioactive compounds offer a cost-effective and less toxic alternative by targeting cancer pathways. This current study aims to identify potential bioactive compounds from silk warm pupa and screen their bioactivity against various cancers through in-silico approaches. Background: Cancer, a disease with substantial worldwide health consequences, is driven by the uncontrolled division and spread of cells. A combination of genetics, environmental factors, and personal lifestyle choices influences its development. Cancer remains a significant global health challenge, driving the need for new therapeutic compounds. Antheraea assamensis Helfer, an edible insect, contains bioactive compounds that may provide a natural approach to reducing cancer progression through dietary intake. Rich in proteins, fatty acids, and bioactive compounds, this insect shows promise in its anti-inflammatory and antioxidant properties. Objective: Currently, available cancer medications are often associated with a range of side effects. Plant-derived compounds present a promising alternative for cancer treatment, offering the potential for fewer side effects. This research aims to identify the most effective bioactive lead molecule for future drug development in the fight against various types of cancer. Methods: To evaluate the therapeutic potential of metabolites from Antheraea assamensis Helfer, various in-silico techniques were used. Molecular docking analysis were conducted to assess the binding affinity and stability of the compounds with cancer-related targets such as EGFR, FGFR, VEGFR1, and mTOR, revealing their inhibitory potential. ADMET analysis predicted the pharmacokinetic properties, including absorption, toxicity, and drug-likeness. In contrast, QSAR analysis forecasted the biological activity of the compounds, helping to quantify their effectiveness in triggering specific biological responses. Results: The molecular docking studies showed promising results, with several bioactive compounds from Antheraea assamensis Helfer exhibiting strong binding affinities to EGFR, FGFR, VEGFR1, and mTOR, suggesting significant inhibitory potential against these cancer-related targets. ADMET analysis further supported these findings by indicating favorable pharmacokinetic properties, such as good absorption, low toxicity, and minimal risk of side effects. QSAR analysis predicted high biological activity for the compounds, reinforcing their potential as effective anticancer agents. Conclusion: The study identifies Antheraea assamensis Helfer as a significant source of bioactive agents like 2-(Dimethylamino) ethyl (9Z,12Z)-octadeca-9,12-dienoate, Echinulin, and Phorbol 12-tiglate 13-decanoate, with promising anticancer activity. In-silico analysis indicates these compounds could inhibit key cancer-related targets like EGFR, FGFR, VEGFR1, and mTOR. Further in-vitro and experimental studies are needed to validate their therapeutic efficacy and safety.

Parkinson's disease is a neurodegenerative condition characterized by the degeneration of dopaminergic neurons, resulting in motor disabilities such as rigidity, bradykinesia, postural instability, and resting tremors. While the exact cause of Parkinson's remains uncertain, both familial and sporadic forms are often associated with the G2019S mutation found in the kinase domain of LRRK2. Roco4 is an analogue of LRRK2 protein in Dictyostelium discoideum which is an established model organism to investigate LRRK2 inhibitors. In this study, the potential treatment of Parkinson's was explored by inhibiting the activity of the mutated LRRK2 protein using Roco4 as the base protein structure. Mongolicain-A and Bacoside-A exhibited significant selectivity towards the G2019S mutation, displaying a binding affinity of - 12.3 Kcal/mol and - 11.4 Kcal/mol respectively. Mongolicain-A demonstrated increased specificity towards Roco4, while Bacoside-A demonstrated significant binding affinity to all 34 kinases proteins alike. The Molecular Dynamics Studies (MDS) results strongly suggests that Mongolicain-A is a significant inhibitor of Roco4 kinase. ADMET and drugability analysis also suggests that among the two best ligands, Mongolicain-A demonstrates significant physicochemical properties to be suitable for best drug like molecule. Based on the in-silico molecular docking, molecular dynamic simulation, ADMET and drugability analyses, it is strongly suggested that, Mongolicain-A could be a potential candidate for treatment and management of Parkinson's disease via inhibition of LRRK2 protein. Further in-vitro and in-vivo investigations are in demand to validate these findings. To identify potential inhibitors, 3069 phytochemicals were screened using molecular docking via AutoDock Vina. Molecular Dynamics Simulation was carried out using GROMACS 2022.2 for a duration of 100ns per complex to study the stability and inhibition potential of the protein ligand complexes. ADMET analysis was carriedout using Molinspiration and preADMET web tool.

Plants are threatened by several diseases caused by phytopathogenic fungi. Melanin is an important pathogenicity factor in some fungal plant diseases. The enzyme 6,3,8-trihydroxynaphthalene reductase (3HNR) is implicated in the catalysis of the melanin biosynthesis in fungi. The chemical fungicide Phthalide acts by inhibiting this enzyme. But despite its efficacy, Phthalide can be detrimental to environmental health, hence the need to look for natural inhibitors to combat phytopathogenic fungi. This study aimed to screen the antifungal activity of some endophytic strains against phytopathogenic fungi of tomato. A total of 7 endophytic fungi were isolated and pre-identified from different parts of celery, parsley, mint, and coriander. On the other hand, five phytopathogenic fungal strains were isolated and pre-identified from tomatoes. The agar cylinder method showed that the endophytic fungi strains Fusarium and Trichoderma have significant inhibitory activity against four phytopathogenic fungi identified as Alternaria and Penicillium. Molecular docking was also used to study the inhibitory effect of some bioactive fungal compounds against the 3HNR enzyme. Drug-likeness and ADMET analyses were conducted on the selected chemicals to test their reliability and pharmaceutical efficacy. Phenylethyl alcohol interacts intensely with the binding site of the 3HNR receptor giving binding energy of -5.3 Kcal/mol, which is close to the co-crystallized ligand Phthalide. In addition, ADMET and pharmacokinetic analysis revealed that Phenylethyl alcohol verify the majority of the filters and pharmacokinetic properties necessary to select an effective antifungal molecule, including Lipinski’s and Veber’s rules.

This study aimed to investigate the effect of fucoidan on the Wnt/β-Catenin pathway using both in-silico molecular docking, molecular dynamics, ADMET analysis (in frizzled-8 receptor and LRP6 coreceptor) and in-vitro experiments using MCF-7 breast cancer cells. Through the molecular docking analysis, the binding energies on the frizzled-8 receptor were −5.6, −5.1, −9.4, and −8.8 kcal/mol, respectively. Meanwhile, those on the LRP6 receptor, were −7.3, −6.2, −10.0, and −9.8 kcal/mol, respectively. The results showed that fucoidan had a favorable binding affinity for both receptors. Furthermore, it was discovered to reduce the interaction and binding affinity between Wnt agonists to frizzled-8 and LRP6 receptors. This reduction was reflected in the change in the binding energy of the fucoidan-Wnt agonist-frizzled 8 and fucoidan-Wnt agonist-LRP6 complexes, which exhibited decreases of −7.0 kcal/mol and −7.8 kcal/mol, respectively. Fucoidan was found stable in complexes with frizzled-8 receptor and co-receptor LRP6. ADMET study showed it’s non-carcinogenic and can be distributed in the body. Fucoidan effectively inhibited β-catenin production, a critical factor in the Wnt/β-catenin pathway. The MCF-7 breast cancer cells were treated with fucoidan extract from S. echinocarpum at incubation times of 24, 48, and 72 h, resulting in a reduction of β-catenin levels by 95.19%, 83.88%, and 80.88%, respectively. Fucoidan also shows no significant difference in value compared to fucoidan standard (F. vesiculosus) and doxorubicin. Fucoidan exhibited antiproliferative effects against breast cancer cells, specifically through its modulation of the Wnt/β-Catenin pathway, and held great potential as an herbal anticancer agent. Communicated by Ramaswamy H. Sarma

Background: The development of antibiotic resistance in bacteria is a matter of global concern due to the exceptionally high morbidity and mortality rates. The outer membrane of most gram-negative bacteria acts as a highly efficient barrier and blocks the entry of the majority of antibiotics, making them ineffective. The Bam complex, β-barrel assembly machinery complex, contains five subunits (BamA, B, C, D, E), which plays a vital role in folding and inserting essential outer membrane proteins into the membrane, thus maintaining outer membrane integrity. BamA and BamD are essential subunits to fulfill this purpose. Therefore, targeting this complex to treat antibiotic resistance can be an incredibly effective approach. Natural bacterial pigments like violacein, phytochemicals like withanone, semasin, and several polyphenols have often been reported for their effective antibiotic, antioxidant, anti-inflammatory, antiviral, and anti-carcinogenic properties. Objective: Structural inhibition of the Bam complex by natural compounds can provide safe and effective treatment for antibiotic resistance by targeting outer membrane integrity. Methods: In-silico ADMET and molecular docking analysis was performed with ten natural compounds, namely violacein, withanone, sesamin, resveratrol, naringenin, quercetin, epicatechin, gallic acid, ellagic acid, and galangin, to analyse their inhibitory potential against the Bam complex. Results: Docking complexes of violacein gave high binding energies of -10.385 and -9.46 Kcal/mol at C and D subunits interface and at A subunits of the Bam complex, respectively. Conclusion: Henceforth, violacein can be an effective antibiotic against to date reported resistant gram-negative bacteria by inhibiting the Bam complex of their outer membrane. Therefore the urgent need for exhaustive research in this concern is highly demanded.

Background: The isatin molecule is present in many natural substances, including plants and animals, and is used to prepare compounds with various biological activities. Objectives: To synthesize a new series of isatin derivatives with the expectation that they will have antimicrobial activity. Methods: Thiazole Schiff bases were synthesized from various Mannich bases of isatin to evaluate their antimicrobial properties. Initially, Mannich bases (2a–e) were synthesized by reacting isatin with formaldehyde and different secondary amines. Subsequently, they were treated with 2-aminothiazole to yield the final compounds (3a–e). Spectroscopic characterization was done via FT-IR and 1H-NMR. The antimicrobial screening was conducted on all derivatives. Molecular docking and ADMET analysis were performed on the final compounds, comparing them with standard drugs (ciprofloxacin and fluconazole). Results: The antimicrobial activity was assessed on two Gram-positive bacteria, Staphylococcus aureus and Bacillus licheniformis; two Gram-negative bacteria, Escherichia coli and Acinetobacter baumannii; and one fungus species, Candida albicans. Molecular docking has recorded higher docking scores for 3d and 3e compared to ciprofloxacin and fluconazole. The virtually active molecules showed an adequate drug-like profile and desired pharmacokinetic properties in the ADMET analysis. Conclusions: Most derivatives displayed significant antimicrobial activity, with compound 3e being the most active, followed by compound 3b. Molecular docking revealed higher scores for compound 3e compared to fluconazole and for compounds 3d and 3e compared to ciprofloxacin. ADMET analysis of compound 3e showed excellent absorption, consistent with its strong GIT absorption.

Bioactive compounds are naturally occurring substances that have the ability to have physiological impacts on the human body. Due to their potential health advantages and their function in preventing and treating a variety of serious health risks, also this substances shown a high antibacterial and antibiofilm activities against bacteria that can affect health. Therefore, the purpose of the current investigation was to test different bioactive compounds (Thymol, Quercetin, Epicatechin gallate, Gallic acid, Coumarin, Caffeic acid, Tannic acid, Apigenin, Carvacrol, Carvone, Beta ionone and Eucalyptol), in order to see there effect against B. cereus. Additionally, the contact angle method was used to examine the influence of those substances on the physicochemical characteristics of PLA 3D printing material and there antiadhesive effect against bacteria studied. According to the antibacterial activities it should be noted that Carvacrol, Tannic acid and Epicatechin gallate were the most active against B. cereus bacteria. The measurements of the contact angle showed a substantial change in the physicochemical characteristics of 3D printing PLA, indicating an improvement in the electron donor character after treatment, and significantly changed the surface hydrophobicity following treatment from hydrophobe PLA to hydrophile PLA after treatement, we can also see that B. cereus can adhere to PLA before treatment but after treatment with bioactive compounds it has become unfavorable which means that our select compounds are indeed active. After the use of computational methods like ADMET analysis, molecular docking and dynamic analysis, it was practical to better understand the physicochemical and pharmacokinetic proprieties, drug-likeness, antibacterial antiadhesive properties of the studied phytocomponents.

In vitro antimicrobial, anticancer evaluation, and in silico studies of mannopyranoside analogs against bacterial and fungal proteins: Acylation leads to improved antimicrobial activity

Lichens are recognized as sources of diverse bioactive metabolites with potential antibacterial properties. This study evaluated the antibacterial activity of Coccocarpia erythroxyli (Spreng.) Swinscow & Krog and its interaction with Penicillin-Binding Protein 3 (PBP3, PDB ID: 6I1E). Methanol extracts of C. erythroxyli were tested against six bacterial strains using the disc diffusion method, revealing moderate antibacterial activity, with the highest inhibition zone observed against Escherichia coli (18.6 ± 0.44 mm), compared to chloramphenicol (29.13 mm). GC-MS analysis identified 33 bioactive compounds, which were further evaluated through in-silico drug-likeness screening and molecular docking. Among these, Cembrene showed the highest binding affinity (−5.9 kcal/mol), interacting with hydrophobic residues PHE182 and TRP185, while the control compound displayed a slightly stronger affinity (−6.3 kcal/mol). These results highlight the moderate antibacterial potential of C. erythroxyli and suggest that its metabolites warrant further investigation as lead compounds in antibacterial drug development, particularly in the context of antibiotic resistance. HIGHLIGHTS The graphical abstract illustrates the workflow of the study on Coccocarpia erythroxyli bioactive compounds as potential antibacterial agents. It begins with the extraction of bioactive compounds from the lichen, followed by in-vitro antibacterial testing. Simultaneously, in-silico molecular docking is conducted to evaluate the interaction of the compounds with PBP3 (6I1E), highlighting key binding sites and interaction energies. The combined results emphasize the potential of these compounds to inhibit bacterial growth and serve as a basis for future drug development targeting resistant bacteria. GRAPHICAL ABSTRACT

Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (−7.5, −7.1, −7.1, and −7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell.

Background:Vepris dainelli (Rutaceae) is an endemic medicinal plant of Ethiopia, traditionally used for the treatment of abdominal cramps, intestinal worms, skin diseases, and tooth pain.Methods:Roots and fruit extracts were subjected to silica gel column chromatographic separation to afford five alkaloids, reported for the first time from the species. The cytotoxic effects of alkaloids (2-4) were evaluated in vitro against the estrogen-responsive MCF-7 and estrogen-unresponsive MDA-MB-231 human breast cancer cell lines by MTS assay.Result:The results revealed that alkaloids (2-4) induced a significant reduction in cell growth of both breast cancer cell lines in a dose-dependent manner. Evodiamine (4) showed the highest potency against the aggressive metastatic MDA-MB-231 cell line at low micromolar concentrations. In addition, it highly arrested the cells in the G2/M phase, especially the MCF-7 cell line. By contrast, evoxanthine (2) and arborinine (3) exhibited higher cytotoxicity against MCF-7 than MDA-MB- 231 and influenced the cell cycle in both cell lines by arresting some cells in the G2/M phase, preventing cells with damaged DNA from entering mitosis. Molecular docking analysis showed that all alkaloids inhibit human topoisomerase II α, compared with vosaroxin’s anti-cancer agent under clinical trial. The ADMET studies revealed that the alkaloids showed the highest drug-likeness properties, suggesting that these alkaloids act as a drug and exhibit remarkable biological activities, except (5). DFT calculations indicated that the studied alkaloids showed the lowest gap energy and were chemically reactive.Conclusion:The results obtained from molecular docking, drug-likeness properties, ADMET analysis, and DFT calculation are in good agreement with experimental studies. Hence, evoxanthine (2), arborinine (3), and evodiamine (4) may serve as lead molecules that could be developed into potent topoisomerase II α inhibitors against human breast cancer cells.

Tuberculosis (TB) remains the second leading cause of death in the world, with the resistance of Mycobacterium tuberculosis to first-line drugs, such as isoniazid (INH), contributing to the emergence of multi-drug resistant TB (MDR-TB). This study aims to evaluate the potential of quercetin and its derivatives as InhA enzyme inhibitors through an in silico approach to offer innovative therapeutic alternatives to improve the effectiveness of TB treatment. The analysis includes physicochemical properties, ADMET profiles, molecular interactions, and affinity of compounds to the InhA enzyme as an antituberculosis target. The study workflow included ligand and receptor preparation, prediction of biological activity, physicochemical and ADMET analysis, docking validation, molecular docking, and visualization of molecular interactions. Molecular docking was performed using Gnina software, showing that rutin has the lowest binding energy (ΔG) of -12.22 kcal/mol, indicating strong interaction affinity. In addition, ADMET and toxicity analysis showed good pharmacokinetic potential for the test compounds Docking validation confirmed the reliability of the employed methodology, further supporting the potential of quercetin and its derivatives as antituberculosis candidates. However, although quercetin and its derivatives showed promising biological activity, the ADMET profile results were variable, requiring further optimization to develop effective and safe TB therapies.

Synthesis, biological evaluation, molecular docking analyses, and ADMET study of azo derivatives containing 1-naphthol against MβL-producing S. maltophilia