Current Enzyme Inhibition - Online First

The SARS-CoV-2 main protease (M^pro) is a critical enzyme for viral replication, making it an essential target for COVID-19 therapeutic development. In this study, we conducted a comprehensive virtual screening campaign to identify natural product-derived M^pro inhibitors using both structure-based pharmacophore modeling and ligand-based similarity search.

Two optimized pharmacophore models were constructed from M^pro crystallographic structures (PDB codes 7QBB and 7TIA), validated through ROC analysis, optimized using Dynophores dynamic simulations, and used to screen two natural product libraries. The ligand-based screening was also performed using the co-crystallized ligands of these models, capturing compounds with high shape and atom-based similarity.

Two rounds of molecular docking were performed to filter and refine the hits, leading to the identification of 17 promising compounds with favorable binding interactions and physicochemical profiles. Molecular dynamics simulations of top hits demonstrated stable binding within the M^pro active site, with binding energies supporting their potential as potent inhibitors.

The integration of dynamic pharmacophore modeling (dynophore) represents a significant advancement over static models by accounting for protein-ligand interaction flexibility during molecular dynamics. This dynamic approach not only improves hit specificity but also reduces false positives, thereby enhancing the reliability of the virtual screening process. Furthermore, the identification of compound 10313 with high binding stability underscores the predictive value of combining pharmacophore filtering with MD simulations.

This study highlights the value of natural products as a reservoir for M^pro inhibitors, presenting novel candidates for further experimental validation in the fight against COVID-19.

Epidermal growth factor receptor (EGFR) protein kinase is a pivotal target in cancer therapy due to its overexpression in various malignancies, including lung, breast, and prostate cancers. Although the FDA has approved several ATP-competitive EGFR inhibitors, their efficacy is often compromised by mutations like T790M and L858R, which enhance ATP affinity and reduce drug binding, thereby further reducing the efficacy of first- and second-generation inhibitors. To overcome these challenges, we aimed to design and evaluate novel curcuminoid derivatives that could potentially serve as more effective EGFR inhibitors.

We designed new curcuminoid derivatives based on an extensive literature review and structure-activity relationship (SAR) analysis. Molecular docking studies were conducted to assess the binding affinities and interaction patterns of these compounds with the EGFR kinase domain. ADME properties were predicted according to Lipinski's Rule of Five. The stability and dynamics of the top-performing compounds were further analysed using molecular dynamics (MD) simulations.

The in-silico studies revealed that compounds with ortho substitutions on the phenyl ring, particularly -Br, -NO2, and -OCH3, exhibited the strongest binding affinities. Notably, compounds 3, 2, and 17 achieved docking scores of -7.23, -7.22, and -7.06, respectively. Additionally, MD simulations confirmed the stability of the Compound 3-EGFR complex, emphasizing the critical role of the α-β-unsaturated ketone aliphatic chain in binding to Met793.

The novel curcuminoid derivatives designed in this study showed strong potential as EGFR inhibitors, with Compound 3 demonstrating superior docking scores and conformational stability comparable to the reference standard, Dacomitinib. These findings suggest that these derivatives could be promising candidates for further development as cancer therapeutics.

Enhydra fluctuans, commonly referred to as water lettuce, is a widely recognized aquatic plant with significant traditional medicinal applications. Its bioactive components have been associated with various pharmacological effects, including antioxidant and anthelmintic properties. This study aimed to assess the potential antioxidant and anthelmintic activities of the aqueous extract of the aerial parts of Enhydra fluctuans.

Preliminary phytochemical screening was conducted to determine the presence of bioactive constituents such as alkaloids, flavonoids, glycosides, phenolic compounds, carbohydrates, saponins, and tannins. Antioxidant activity was evaluated using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay, where the IC50 values of the aqueous extract and standard ascorbic acid were compared. The anthelmintic activity was assessed using the earthworm (Eisenia fetida) at three different extract concentrations (25, 50, and 100 mg/ml). Albendazole (10 mg/ml) served as the standard reference, while normal saline acted as the control. Parameters such as time to paralysis and time to death were recorded. Additionally, biochemical and histopathological analyses of the gut were performed to validate the findings.

Phytochemical analysis confirmed the presence of multiple bioactive compounds, supporting the plant's medicinal potential. The aqueous extract exhibited significant antioxidant activity with an IC50 value of 23.29 µg/ml, closely comparable to that of ascorbic acid (27.73 µg/ml). The anthelmintic activity demonstrated a dose-dependent effect, with the 100 mg/ml extract showing a paralysis time of 18 ±1.52 minutes and a death time of 76 ±1.28 minutes. Comparatively, albendazole-treated worms exhibited a paralysis time of 18.32 ±2.64 minutes and a death time of 54.24 ±2.18 minutes. Biochemical and gut histopathological examinations further corroborated the extract's efficacy in anthelmintic activity.

These findings highlight the potent antioxidant and anthelmintic properties of the plant's aqueous extract, demonstrating its efficacy comparable to standard drugs. The results support the plant’s therapeutic potential and warrant further investigation into its active constituents and mechanisms of action.

The study confirms the antioxidant and anthelmintic potential of the aqueous extract of Enhydra fluctuans. The significant free radical scavenging activity and dose-dependent anthelmintic effects support its traditional medicinal use. These findings provide a scientific basis for further exploration of Enhydra fluctuans as a natural therapeutic agent, particularly in developing plant-based anthelmintic treatments.

Ficus palmata is a herbaceous perennial plant belonging to the family Moraceae. It is used in various diseases, e.g., gastrointestinal disorders, tumours, hypoglycaemia, ulcers, hyperlipidaemia, diabetes, and fungal infections.

The fruit of the Ficus palmata plant was extracted. The total phenolic and total flavonoid content were determined. Following column chromatography, phytoconstituents were isolated and identified by mass spectroscopy, FTIR, and NMR. The antioxidant activity of phytoconstituents was evaluated, and molecular docking studies were performed against the H⁺K⁺-ATPase enzyme and H2 Receptor.

The extract from Ficus palmata yielded rich in flavonoids and phenolic content. Isolation of compounds was done and characterized to be rutin and luteolin. The further evaluation of the antioxidant activity of compounds demonstrated significant activity with an IC50 value indicating strong free radical scavenging activity. Molecular docking studies were performed against the H⁺K⁺-ATPase enzyme and H2 Receptor, revealing that both compounds exhibit high binding affinity and favourable interactions with key sites.

The study revealed that Ficus palmata fruit extract is a rich source of flavonoids and phenolics, notably rutin and luteolin. These compounds demonstrated strong antioxidant activity through various free radical scavenging assays. Molecular docking suggested their potential as inhibitors of the H⁺K⁺-ATPase enzyme and H2 receptor, indicating antiulcer potential. These findings support the therapeutic relevance of Ficus palmata in oxidative stress-related gastric disorders.

The findings suggest that the isolated compounds rutin and luteolin possess potential antioxidant activity and could be a potential therapeutic target for the H⁺K⁺-ATPase enzyme and H2 Receptor.

Heterocyclic compounds containing oxygen, nitrogen, and/or sulfur atoms are of significant importance in drug discovery and development. Pyrazole moieties, in particular, have broad applications across various fields, including herbicides, corrosion inhibitors, electron transport materials, polymers, and luminescent materials. This underscores the growing need in medicinal chemistry to design new anticancer agents that improve therapeutic efficacy and safety.

A series of novel pyrazole-naphthalene derivatives were synthesized from chalcones, which were obtained through an aldol condensation between benzaldehyde and acetophenone, followed by a Claisen-condensation reaction. All the synthesized compounds were characterized by NMR and IR spectrum examinations, as well as C, H, and N analyses. The synthesized compounds were screened for biological activity against the breast cancer cell line (MCF-7 strain) using an MTT assay. Furthermore, a molecular docking study was performed to elucidate the binding modes of synthesized ligands in the active pockets of the three-dimensional crystallographic structure of CDK2 in complex with inhibitor RC-1-148 (PDB ID: 3QTR) for further predicting the mechanism of action.

Molecules R5, R8, and R9 were found to be the most active compounds in the series, exhibiting sensitivity of up to 5.0 μg/ml. Additionally, compounds R8, R13, and R10 demonstrated activity against cancer cells, with sensitivity reaching up to 3.2 μg/ml.

This study presents a promising class of pyrazole-naphthalene derivatives with significant anticancer activity, particularly against the MCF-7 breast cancer cell line. The combined biological screening and molecular docking suggest that these compounds could serve as potential lead candidates for further development in anticancer drug discovery.

The current study highlights the unique structural characteristics and significant biological activity of the synthesized compounds. In the pursuit of novel anticancer molecules, these compounds could prove beneficial to society.

The present study investigates the structural and functional attributes of HCN synthase, known for its role in metals recovery from natural and secondary sources and gaining attention in the field of biohydrometallurgy.

The nucleotide sequences of 23 bacterial strains in reference to Pseudomonas aeruginosa were procured from the UniPROT and were subjected to analyses using SWISS-MODEL, PDBsum, ESBRI, MEME, InterProScan, and MEGA X.

Multiple sequence alignment showed a total of sixteen 100% conserved positions in the aligned region. The physico-chemical characteristics showed molecular weight between 39.24–46.79 kDa, pI range of 4.99–10.43, instability index from 26.69–50.66, and aliphatic index ranging from 83.07-101.59. The amino acid contents - Leucine (10.3%), Alanine (9.8%), Glycine (9.3%), Valine (6.8%), and Glutamic acid (6.3%) were found predominantly. The secondary structure revealed that the enzyme is dominated by 37.44% of amino acid residues in random coils, 36.97% in alpha-helices and 17.50% in extended sheets.

The secondary structure prediction revealed that the enzyme consists of twelve α-helices that interact through nineteen helix-helix interactions along with twenty-three beta strands and three gamma turns. Moreover, the tertiary structure prediction showed the structural stability, consistency, and reliability of the HCN synthase protein. In addition, functional analysis unveiled the transmembrane regions, protein-protein interactions, post-translational modifications, and phosphorylation sites of the protein.

Fundamentally, the study uncovered valuable perspectives on a stable and consistent structure of HCN synthase, providing significant insights into its characteristics.

Thus, the present study improves the understanding of HCN synthase and offers a foundation for future research.

Breast cancer is the most prevalent cancer among women globally, characterized by the uncontrolled growth of breast cells, and remains a leading cause of cancer-related morbidity and mortality. It can occur in both men and women, though it is significantly rarer in men. The multifactorial nature of breast cancer involves genetic mutations, hormonal influences, and complex cellular signalling pathways. The disease is typically classified into different subtypes based on hormone receptor status, which influences treatment decisions. Early detection through regular screening, such as mammograms, and awareness of symptoms significantly improve prognosis. Treatment options vary based on the stage and type of breast cancer and may include surgery, radiation therapy, chemotherapy, hormone therapy, and targeted therapy. We aimed to design novel compounds based on reported active pharmacophoric features and validate them through molecular modelling. These designed compounds were then synthesized and characterized. Finally, a biological evaluation of the synthesized compounds was performed to assess their efficacy.

Thirty compounds were designed based on a literature survey. Out of these compounds, twelve compounds were found good on the docking studies, and these twelve new derivatives (RD 01-12) were synthesized and subjected to in silico, in vitro (EGFR assay), and ADMET profiling to identify the most potent compound.

All 12 compounds were synthesised and characterised. Out of 12 compounds, RD-09 emerged as the most potent enzymatic assay with an IC50 value of 1.21 ± 0.03 µM, confirmed by docking studies; it possessed a docking score of -7.302 against the EGFR receptor. These compounds were further characterized using IR, ¹H NMR, and mass spectrometry.

Based on pharmacophoric features, twelve triazine-4-thiazolidinone derivatives (RD 01-12) were designed, synthesized, and evaluated for their potential as EGFR-2 inhibitors, specifically targeting triple-negative breast cancer (TNBC). Among 12 synthesised compounds, compound RD-09 demonstrated the most significant activity with an IC50 value of 1.21 ± 0.03 µM. Docking studies further supported its binding interaction with the catalytic domain of the EGFR receptor. The combined results from in vitro, in silico, and ADMET profiling suggest that RD-09 holds promise as a leading compound for further development in the treatment of TNBC.