Promising Binding Affinity Research Articles

Hybrid Molecules Containing Methotrexate, Vitamin D, and Platinum Derivatives: Synthesis, Characterization, In Vitro Cytotoxicity, In Silico ADME Docking, Molecular Docking and Dynamics.

Designing hybrid-based drugs is one promising strategy for developing effective anticancer drugs that explore combination therapy to enhance treatment efficacy, overcome the development of drug resistance, and lower treatment duration. Bisphosphonates and Vitamin D are commonly administered drugs for the treatment of bone diseases and the prevention of bone metastases. Platinum-based and methotrexate are widely used anticancer drugs in clinics. However, their use is hampered by adverse side effects. Hybrid-based compounds containing either bisphosphonate, vitamin D, platinum-based, or methotrexate were synthesized and characterized using FTIR, 1H-,31P, 13C-NMR, and UHPLC-HRMS which confirmed their successful synthesis. The hydroxyapatite bone binding assay revealed a promising percentage binding affinity of the bisphosphonate hybrid compounds. In vitro cytotoxicity assays on MCF-7 and HT-29 cell lines revealed a promising cytotoxic effect of hybrid 19 at 50 and 100 μg/mL on HT-29 and hybrid 15 on MCF-7 at 100 μg/mL. Molecular docking and dynamics simulation analysis revealed a binding affinity of -9.70 kcal/mol for hybrid 15 against Human 3 alpha-hydroxysteroid dehydrogenase type 3, showing its capability to inhibit Human 3 alpha-hydroxysteroid dehydrogenase type 3. The Swiss ADME, ProTox-II, GUSAR (General Unrestricted Structure-Activity Relationships), and molecular docking and dynamics studies revealed that these compounds are promising anticancer compounds.

Amide Functionalized Novel Pyrrolo-pyrimidine Derivative as Anticancer Agents: Synthesis, Characterization and Molecular Docking Studies.

The development of new therapies targeting crucial kinases involved in cancer progression is a promising area of research. Pyrazolo pyrimidine derivatives have emerged as potential candidates for this purpose. This study aims to synthesize pyrazolo pyrimidine derivatives (5a-5r), evaluate their molecular docking against key kinases, and assess their anticancer activity. The synthesis involved a multi-step procedure starting with the cyclization of 6-amino-2- methylpyrimidin-4(3H)-one (1) to form 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-ol (2). This was followed by chlorination to yield 4-chloro-2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidine (3) and nucleophilic substitution to produce 2-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-4-amine (4). The final derivatives (5a-5r) were synthesized through amide bond formation with various carboxylic acids using DCC and DMAP. Structural elucidation was confirmed via NMR, mass spectrometry, and HRMS. Molecular docking studies were conducted against Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and cyclin-dependent kinase 4 (CDK4). Anticancer activity was evaluated against MCF-7, SET-2, and HCT-116 cell lines. Structural elucidation confirmed the successful synthesis of the derivatives. Molecular docking studies revealed promising binding affinities for selected derivatives, particularly those with heterocyclic substitutions. Anticancer activity evaluation showed diverse potency profiles, with several derivatives demonstrating IC50 values comparable to the reference drug, doxorubicin. Derivatives featuring nitro and heterocyclic moieties exhibited significant anticancer activity. The synthesized pyrazolo pyrimidine derivatives showed potential as lead compounds for further development due to their promising binding affinities and significant anticancer activity, particularly those with nitro and heterocyclic moieties.

Network pharmacology to unveil the mechanism of Astragali Radix in the treatment of lupus nephritis via PI3K/AKT/mTOR pathway

We used network pharmacology, molecular docking, and in vitro experiments to explore the mechanisms of Astragali Radix in the treatment of lupus nephritis. We screened compounds and targets of Astragali Radix, as well as related genes of lupus nephritis from databases. We identified 211 common genes and 44 compounds between the herb and the disease, and constructed global, narrowed, hierarchical Compound-Target Interaction networks to illustrate the possible mechanism. We found that the PI3K/AKT/mTOR pathway is a core target gene set identified through enrichment analysis, PPI analysis and MCODE analysis. In vitro experiments showed that freeze-dried Astragali powder inhibits activation of PI3K, AKT1 and mTOR in TGF-β1 stimulated HK-2 cells. Molecular docking demonstrated that (R)-isomucronulatol, 3,9,10-trimethoxypterocarpan and astrapterocarpan exhibited promising binding affinity to PI3K, AKT, and mTOR proteins.

Structural and free energy landscape analysis for the discovery of antiviral compounds targeting the cap-binding domain of influenza polymerase PB2

Influenza poses a significant threat to global health, with the ability to cause severe epidemics and pandemics. The polymerase basic protein 2 (PB2) of the influenza virus plays a crucial role in the viral replication process, making the CAP-binding domain of PB2 an attractive target for antiviral drug development. This study aimed to identify and evaluate potential inhibitors of the influenza polymerase PB2 CAP-binding domain using computational drug discovery methods. We employed a comprehensive computational approach involving virtual screening, molecular docking, and 500 ns molecular dynamics (MD) simulations. Compounds were selected from the Diverse lib database and assessed for their binding affinity and stability in interaction with the PB2 CAP-binding domain. The study utilized the generalized amber force field (GAFF) for MD simulations to further evaluate the dynamic behaviour and stability of the interactions. Among the screened compounds, compounds 1, 3, and 4 showed promising binding affinities. Compound 4 demonstrated the highest binding stability and the most favourable free energy profile, indicating strong and consistent interaction with the target domain. Compound 3 displayed moderate stability with dynamic conformational changes, while Compound 1 maintained robust interactions throughout the simulations. Comparative analyses of these compounds against a control compound highlighted their potential efficacy. Compound 4 emerged as the most promising inhibitor, with substantial stability and strong binding affinity to the PB2 CAP-binding domain. These findings suggest that compound 4, along with compounds 1 and 3, holds the potential for further development into effective antiviral agents against influenza. Future studies should focus on experimental validation of these compounds and exploration of resistance mechanisms to enhance their therapeutic utility.

In Silico Analysis of Vitamin D Interactions with Aging Proteins: Docking, Molecular Dynamics, and Solvation Free Energy Studies

Aging is a natural process that is also influenced by some factors like the food someone eats, lifestyle decisions, and impacts on general health. Despite the recognized role of nutrition in modulating the molecular and cellular mechanisms underlying aging, there is a lack of comprehensive exploration into potential interventions that can effectively mitigate these effects. In this study, we investigated the potential anti-aging properties of vitamin D by examining its interactions with key molecular targets involved in aging-related pathways. By using molecular docking and dynamics techniques, we evaluate the interactions and stability of vitamins D2 and D3 with key proteins involved in aging pathways, such as SIRT1, mTOR, AMPK, Klotho, AhR, and MAPK. Our results reveal promising binding affinities between vitamin D and SIRT1 forms, with energy values of −48.33 kJ/mol and −45.94 kJ/mol for vitamins D2 and D3, respectively, in aqueous environments. Moreover, molecular dynamics simulations revealed that the vitamin D3–SIRT1 complex exhibited greater stability compared with the vitamin D2–SIRT1 complex. The study calculated the solvation free energy to compare the solubility of vitamins D2 and D3 in water and various organic solvents. Despite their strong interactions with water, both vitamins exhibited low solubility, primarily due to the high energy cost associated with cavity formation in the aqueous environment. Compared with other solvents, water demonstrated particularly low solubility for both vitamins. This suggested that vitamins D2 and D3 preferred binding to aging receptors over dissolving in bulk aqueous environments, supporting their strong therapeutic interactions with these receptors. These findings shed light on the molecular mechanisms underlying vitamin D’s potential anti-aging effects and lay the groundwork for developing nutraceuticals targeting aging and associated diseases. Understanding these mechanisms holds promise for future interventions aimed at promoting healthy aging and enhancing overall well-being.

Exploring potential biomarkers and lead molecules in gastric cancer by network biology, drug repurposing and virtual screening strategies.

Gastric cancer poses a significant global health challenge, necessitating innovative approaches for biomarker discovery and therapeutic intervention. This study employs a multifaceted strategy integrating network biology, drug repurposing, and virtual screening to elucidate and expand the molecular landscape of gastric cancer. We identified and prioritized key genes implicated in gastric cancer by utilizing data from diverse databases and text-mining techniques. Network analysis underscored intricate gene interactions, emphasizing potential therapeutic targets such as CTNNB1, BCL2, TP53, etc, and highlighted ACTB among the top hub genes crucial in disease progression. Drug repurposing on 626 FDA-approved drugs for digestive system-related cancers revealed Norgestimate and Nimesulide as likely top candidates for gastric cancer, validated by molecular docking and dynamics simulations. Further, combinatorial synthesis of scaffold libraries derived from known chemotypes generated 56,160 virtual compounds, of which 76 new compounds were prioritized based on promising binding affinities and interactions at critical residues. Hotspot residue analysis identified GLU 214 and others as essential for ligand binding stability, enhancing compound efficacy and specificity. These findings support the therapeutic potential of targeting beta-actin protein in gastric cancer treatment, suggesting a future for further experimental validation and clinical translation. In conclusion, this study highlights the potential of repurposable drugs and virtual screening which can be used in combination with existing anti-gastric cancer drugs for gastric cancer therapy, emphasizing the role of computational methodologies in drug discovery.

In-silico ADME Evaluation and Molecular Docking of a Novel Compound’ 2-(4-Allylpiperazin-1-Yl)-1-(1-(4-Nitrophenyl)-1h-Tetrazol-5-Yl) Ethanone’ as Potential Antimicrobial Agents.

Molecular docking serves as a pivotal tool in comprehending drug-receptor interactions within modern-day drug design. In a previous report, new compounds 2-(4-allylpiperazin-1-yl)-1-(1-aryl-1H-tetrazol-5-yl) etalons were analyzed. Among these compounds, ‘2-(4-allylpiperazin-1-yl)-1-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)ethanone’ was singled for molecular docking as it shows dual antibacterial and antifungal studies. Docking investigations revealed promising binding affinity of the compound towards Escherichia coli (1KZN), exhibiting significant antibacterial activity of docking grade -5.53 Kcal/mol, indicative of a fortified binding interaction. Conversely, the compound exhibited weaker binding affinity towards Candida albicans (1AI9) with a docking grade of -0.72 Kcal/mol. Negative binding energy signifies a robust alignment between the ligand and target protein, suggesting potential therapeutic efficacy against microbial activity. Moreover, in-silico ADMET calculations were conducted, and the synthesized compound confirms the drug-likeness within the defined parameters: molecular weight between 150 to 500 g/mol, TPSA polarity between 20 to 130 Å2 , lipophilicity ranging between -0.7 to +5.0 Log S not exceeding 6, flexibility not exceeding 9, and saturation not inferior to 0.25. The compound demonstrated compliance with these criteria, suggesting favorable in-vivo drug absorption and permeation characteristics.

Molecular descriptors and in silico studies of 4-((5-(decylthio)-4-methyl-4n-1,2,4-triazol-3-yl)methyl)morpholine as a potential drug for the treatment of fungal pathologies

The article explores the polypharmacological profiling of 4-((5-(decylthio)-4-methyl-4H-1,2,4-triazole-3-yl)methyl)morpholine as a potential antimicrobial agent. The study utilized 15148 electronic pharmacophore models of organisms, ranked by the Tversky index. Detailed analysis revealed classical bonding patterns with selected enzymes, identifying key amino acid residues involved in complex formation. Protein target prediction was conducted through various stages using the Galaxy web service, including ligand structure creation, pharmacophore alignment, and target ranking. The activities of the molecules against 1G6C, 2W6O, 3G7F, 3OWU, 4IVR, and 4TZT proteins were compared. Docking studies with PyMOL and Discovery Studio Visualizer revealed binding to thymidine kinase, thiamine phosphate synthase, and biotin carboxylase with promising binding affinities. These interactions suggest potential antibacterial and antiviral effects, warranting further virtual screening and in-depth studies for the development of effective antimicrobial drugs. Calculations of the molecules were made with the gaussian package program. Calculations were made on the 6-31++g** basis set at B3LYP, HF, and M062X levels with Gaussian software. Afterwards, the 0–100 ns interaction of the molecule with the highest activity was examined.

In-Vitro and In-Silico Studies of Brevifoliol Ester Analogues against Insulin Resistance Condition.

Brevifoliol is a diterpenoid that occurs naturally in the plants of Taxus genus and is widely used as chemotherapy agent for the management of cancer. A series of semisynthetic esters analogues of brevifoliol were prepared by Steglich esterification and attempted for their pharmacological potential against insulin resistance conditions using in-vitro and in-silico assays. The aim of this study is to understand the pharmacological potential of eighteen semisynthetic analogs through Steglich esterification of Brevifoliol against insulin resistance condition Methods: In the in-vitro study, insulin resistance condition was induced in skeletal muscle cells using TNF-α, pro-inflammatory cytokine and these cells were treated with brevifoliol analogues. The most potent analouge was further validated using in-silico docking study against the tumor necrosis factor (TNF-α) (PDB ID: 2AZ5) and Human Insulin Receptor (PDB ID: 1IR3), using the Auto dock Vina v0.8 program. Although, all the analogues of Brevifoliol significantly exhibited the pharmacological potential. Among all, analogue 17 was most potent in reversing the TNF-α induced insulin resistance condition in skeletal muscle cells and also to inhibit the production of TNF-α in LPSinduced inflammation in macrophage cells in a dose-dependent manner. Similarly, in-silico molecular docking studies revealed that analogue 17 possesses a more promising binding affinity than the selected control drug metformin toward the TNF-α and insulin receptor. These findings suggested the suitability of analogue 17 as a drug-like candidate for further investigation toward the management of insulin resistance conditions.

Design, Docking, Synthesis, and In vitro Evaluation of Potent Anti-tubercular Agents Targeting DNA Gyrase

Background: Tuberculosis caused by Mycobacterium tuberculosis has been reported to infect about two-third of the global population and to continuously develop multidrug resistance. DNA gyrase, a type II topoisomerase, is a promising target of the quinolone class of drugs in the treatment of tuberculosis. Objective: The present study is focused on the design and synthesis of newer nitrogen heterocyclics containing indole, n-methyl piperazine, piperidine, and pyrrolidine ring structures. Methods: Initially designed compounds were evaluated for their affinity to the DNA gyrase target. The molecular docking performed using FlexX indicated compounds IIb5 (1-(R)-(4-hydroxyphenyl)(4- methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)urea and IIc5 ((1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin- 1-yl)methyl) thiourea to exhibit promising binding affinity (dock score of -15.01 and -13.77) respectively when compared to the reference MFX moxifloxacin (dock score -4.40) with the target 5BS8 (DNA gyrase). Further, the best 10 compounds were synthesized by one-pot synthesis employing the reaction of indole/N-methyl piperazine/piperidine/pyrrolidine with N-substituted benzaldehydes in the presence of acetamide/urea/thiourea to afford the compounds in 54.60% to 85.47% yield. The synthesized compounds were suitably characterized using chromatographic and spectroscopic tools. Results: In the microplate Alamar Blue assay (MABA), compounds IIb1, IIIc2, IIIb1, and IIb5 exhibited good minimum inhibitory concentrations of 1.6 μg/mL, 3.12 μg/mL, and 12.5 μg/mL, respectively, when compared to the standard rifampicin with 0.8 μg/mL inhibitory concentration. The MTB gyrase supercoiling assay performed using Mycobacterium tuberculosis gyrase supercoiling assay kit demonstrated compound IIb5 at a concentration of 300 μg/mL to show gyrase inhibition in comparison to MFX at 60 μg/mL. In the MTT assay performed using the human breast cancer cell line MCF-7, compounds IIc2, IIb5, and IIb1 showed IC50 values of 2.57 μM, 12.54 μM, and 12.75 μM, respectively, compared to doxorubicin (1.10 μM) at 7-48 hrs and 72 hrs of the study. Conclusion: Based on these observations, N-methyl piperazine class of compounds can serve as a lead/pharmacophore for the rational design of potent molecules against MTB gyrase to combat the growing issue of MDR-TB.

In silico and in vitro screening of selected antimicrobial compounds for inhibiting drug efflux pumps to combat threatening MRSA

The rapid emergence of antibiotic-resistant bacteria is occurring worldwide due to severe antibiotic abuse in the past few decades; among them, Methicillin-resistant Staphylococcus aureus (MRSA) is of major concern. Study examines potent antimicrobial compounds against Methicillin resistance Staphylococcus aureus (MRSA) efflux system. Interactome data serves as a primary focal point for global MRSA infection control initiatives. We employed CB Dock and Discovery Studio for performing docking analysis on specific antimicrobial compounds against NorA, NorB, and NorG. Additionally, we conducted molecular dynamics simulations using myPresto. In vitro validation was done by agar-based EtBr cartwheel method to assess the efflux pump activity of MRSA. Out of the eight screened antimicrobial compounds, quercetin exhibited favorable binding energies. Subsequently, molecular dynamics simulations were conducted on quercetin complexes with NorA, NorB, and NorG. In vitro result revealed that the quercetin is active at concentration of 60 µg/ml ±10 against MRSA to inhibit efflux mechanisms. Quercetin demonstrated the most promising binding affinity with the efflux pumps and their regulators of MRSA, making it the prime candidate for use with antibiotics. In-vivo experiments must be performed to validate the in-silico and in vitro analysis.

Biosynthesis and Characterization of Aeonium arboreum-Derived Silver Nanoparticles: Antimicrobial Activity, Biofilm Inhibition, Antihemolytic Activity, and In Silico Studies.

Environmentally friendly biosynthesis of silver nanoparticles (AgNPs) from Aeonium arboreum (L.) Webb & Berthel is reported for the first time. The synthesized AgNPs were characterized using UV-Vis, FTIR, TEM, Zeta potential, and XRD analysis, revealing high stability (-29.1 mV), spherical shape, and an average size of 100 nm. The antimicrobial activity levels of both A. arboreum extract and biosynthesized AgNPs were evaluated against five uropathogens (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans). Both the extract and the AgNPs exhibited significant efficacy, particularly against E. coli, with inhibition zones of 27 mm and 30 mm, respectively. LC-MS analysis tentatively identified 11 secondary metabolites in the extract, including quercetin-3-O-glucoside, quercetin-3-O-rhamnoside, myricetin 3-glucoside, and daphneresinol. In silico docking studies revealed promising binding affinities of these metabolites in relation to key enzymes involved in bacterial folate synthesis (dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS)) and DNA replication (DNA gyrase). These findings demonstrate the potential of A. arboreum-based AgNPs and their associated metabolites as a novel therapeutic approach for combating urinary tract infections. Their antimicrobial, antihemolytic, and antibiofilm properties warrant further investigation.

Camptothecin and its Analogues as Putative Bruton Tyrosine Kinase (BTK) Inhibitors in Cancer Therapy - Biophysical Simulations of Wild Type and C481S Mutation

Camptothecin (CPT) and its derivatives are extracted from the Chinese tree Camptotheca acuminata and have been long known for their significant antitumor activity. The widely reported primary mechanism of their anti-cancer activity is through inhibition of topoisomerase I (Topo I), a key anticancer target. However, there is a lack of research on other possible mechanisms of action of CPT and its analogues (CPT/analogues). In this report, we investigated the potential inhibitory mechanism of CPT/derivatives against Bruton’s tyrosine kinase (BTK) ‒ a crucial protein for regulating various cellular functions and is essential for B-cell growth and cyclical division. The binding mechanism of CPT and its analogues (Irinotecan, Diflomotecan, and Topotecan) against BTK was investigated using molecular docking, molecular dynamics simulations and thermodynamic binding free energy calculations. NRX-0492, a potent orally active degrader of both wild-type and mutant BTK, was used as a reference/control inhibitor. We also included a set of active binders (actives) and non-binders (inactives) to distinguish between effective binders and false positives to ensure the validity of our results. Binding affinity analysis suggested that CPT and its analogues could potentially bind to BTK comparably to NRX-0492. The studied compounds demonstrated stable binding with the protein throughout the simulation time via hydrogen bonds, π-π interactions, van der Waals forces and π-sulfur interactions. Irinotecan exhibited a binding affinity of ΔGbinding = –42.4±5.3 kcal/mol, closely matching that of NRX-0492 (ΔGbinding = –48.8±3.4 kcal/mol). Furthermore, the activity of CPT/derivatives was examined against the C481S mutant. Although the activity was slightly decreased due to the mutation, the compounds retained a promising binding affinity when compared to the results of NRX-0492. The findings of this study provide foundation for future experimental investigation of unexplored potential anti-cancer mechanism of CPT/derivatives and offer a new perspective on repurposing of natural products in cancer therapy.

In vitro and in silico assessment of antidiabetic and antioxidant potencies of secondary metabolites from Gymnema sylvestre

This study investigated the chemical constituents, antioxidant potential, and in vitro and in silico antidiabetic activity of Gymnema sylvestre. Column chromatography and spectroscopic techniques identified twelve compounds from the methanol extract, including 4 sterols (1–4), 5 triterpenoids (5–9), and 3 flavonoids (10–12). The chemophenetic significance of all compounds was also investigated. The antioxidant capacity of the extract and compounds (1–4) was evaluated using FRAP and DPPH assays. The extract exhibited strong free radical scavenging activity (IC50 = 48.34 µg/mL), while compounds (1–4) displayed varying degrees of efficacy (IC50 = 98.30–286.13 µg/mL). The FRAP assay indicated significant reducing power for both extract and compounds (58.54, 47.61, 56.61, and 49.11 mg Eq.VitC/g for extract and compounds 1 &2, 3, and 4, respectively). The antidiabetic potential was assessed through α-amylase and α-glucosidase enzyme inhibition assays. The crude extract demonstrated the most potent inhibition (IC50 = 218.46 and 57.42 µg/mL for α-glucosidase and α-amylase respectively) suggesting its potential for managing postprandial hyperglycaemia. In silico studies employed molecular docking and dynamics simulations to elucidate the interactions between identified compounds and α-amylase/α-glucosidase enzymes. The results revealed promising binding affinities between the compounds and target enzymes, with compound 6 demonstrating the highest predicted inhibitory activity with −10 kcal/mol and −9.1 kcal/mol for α-amylase and α-glucosidase, respectively. This study highlights the presence of diverse bioactive compounds in Gymnema sylvestre. The extract exhibits antioxidant properties and inhibits carbohydrate-digesting enzymes, suggesting its potential as a complementary therapeutic approach for managing hyperglycaemia associated with type 2 diabetes.

Identification of South African Plant-Based Bioactive Compounds as Potential Inhibitors against the SARS-CoV-2 Receptor.

The expected progress in SARS-CoV-2 vaccinations, as anticipated in 2020 and 2021, has fallen short, exacerbating global disparities due to a lack of universally recognized "safe and effective" vaccines. This study focuses on extracts of South African medicinal plants, Artemisia annua and Artemisia afra, to identify metabolomic bioactive compounds inhibiting the binding of the SARS-CoV-2 spike protein to ACE2 receptors. The extracts were monitored for cytotoxicity using a resazurin cell viability assay and xCELLigence real-time cell analyzer. Chemical profiling was performed using UPLC-MS/MS, orthogonal projection to latent structures (OPLS), and evaluated using principle component analysis (PCA) models. Identified bioactive compounds were subjected to in vitro SARS-CoV-2 enzyme inhibition assay using standard methods and docked into the spike (S) glycoprotein of SARS-CoV-2 using Schrodinger® suite followed by molecular dynamics simulation studies. Cell viability assays revealed non-toxic effects of extracts on HEK293T cells at lower concentrations. Chemical profiling identified 81 bioactive compounds, with compounds like 6″-O-acetylglycitin, 25-hydroxyvitamin D3-26,23-lactone, and sesaminol glucoside showing promising binding affinity. Molecular dynamics simulations suggested less stable binding, but in vitro studies demonstrated the ability of these compounds to interfere with SARS-CoV-2 spike protein's binding to the human ACE2 receptor. Sesaminol glucoside emerged as the most effective inhibitor against this interaction. This study emphasizes the importance of multiplatform metabolite profiling and chemometrics to understand plant extract composition. This finding is of immense significance in terms of unravelling metabolomics bioactive compounds inhibiting the binding of the SARS-CoV-2 spike protein to ACE2 receptors and holds promise for phytotherapeutics against SARS-CoV-2.

Precision Drug Repurposing: A Deep Learning Toolkit for Identifying 34 Hyperpigmentation-Associated Genes and Optimizing Treatment Selection.

Hyperpigmentation is a skin disorder characterized by a localized darkening of the skin due to increased melanin production. When patients fail first line topical treatments, secondary treatments such as chemical peels and lasers are offered. However, these interventions are not devoid of risks and are associated with postinflammatory hyperpigmentation. In the quest for novel therapeutic potentials, this study aims to investigate computational methods in the identification of new targeted therapies in the treatment of hyperpigmentation. We used a comprehensive approach, which integrated text mining, interpreting gene lists through enrichment analysis and integration of diverse biological information (GeneCodis), protein-protein association networks and functional enrichment analyses (STRING), and plug-in network centrality parameters (Cytoscape) to pinpoint genes closely associated with hyperpigmentation. Subsequently, analysis of drug-gene interactions to identify potential drugs (Cortellis) was utilized to select drugs targeting these identified genes. Lastly, we used Deep Learning Based Drug Repurposing Toolkit (DeepPurpose) to conduct drug-target interaction predictions to ultimately identify candidate drugs with the most promising binding affinities. Thirty-four hyperpigmentation-related genes were identified by text mining. Eight key genes were highlighted by utilizing GeneCodis, STRING, Cytoscape, gene enrichment, and protein-protein interaction analysis. Thirty-five drugs targeting hyperpigmentation-associated genes were identified by Cortellis, and 29 drugs, including 16 M2PK1 inhibitors, 11 KRAS inhibitors, and 2 BRAF inhibitors were recommended by DeepPurpose. The study highlights the promise of advanced computational methodology for identifying potential treatments for hyperpigmentation.

Interaction and binding mechanism of anticancer echinacoside phenylethanoid glycoside against hepatocellular carcinoma with subdomains of human serum albumin

A phenylethanoid glycoside known as echinacoside has demonstrated promising anticancer properties against numerous cancer cell types. However, its pharmacokinetics or anticancer mechanism has remained unclear. Herein, the interaction of the echinacoside with human serum albumin (HSA) was explored by intrinsic/extrinsic fluorescence spectroscopy, circular dichroism (CD) spectroscopy as well as molecular docking simulation. Also, the anticancer effects and possible mechanism of action of the echinacoside against hepatocellular carcinoma (HCC) cells, MHCC-97-H with high tumorgenicity and metastasis, were assessed by cell viability, flow cytometry, qRT-PCR, and western blot assays. The results showed a static quenching mechanism in the formation of echinacoside-HSA complex, one binding site on HSA for echinacoside, contribution of hydrophobic interactions (PHE157, GLU188 and PRO447), and slight conformational changes of HSA in the complex form. Cellular assays disclosed that treatment with echinacoside concentration-dependently mitigated the proliferation of MHCC97-H cells in vitro with an IC50 concentration of around 30 µM. Also, echinacoside triggered apoptosis through the regulation of caspase-3 at mRNA and protein levels. Moreover, echinacoside reduced the expression of astrocyte elevated gene-1 (AEG-1)and N-cadherin, while enhancing the expression of E-cadherin, as the main hallmarks of epithelial–mesenchymal transition (EMT) in tumorigenicity and metastasis. Therefore, these data indicated that echinacoside with a promising binding affinity with HSA in a mimicking physiological condition may inhibit the proliferation and metastatic activity of MHCC97-H cells mediated by manipulation of the AEG-1/EMT pathway.

Quercetin derivatives as potential inhibitors of Nipah virus phosphoprotein through in silico drug design approaches

The Nipah virus (NiV) is a pathogenic infection presenting a substantial risk to both human and animal communities. Despite its virulence, there are currently no available drugs or vaccines for NiV. To fight against this challenge, we applied a multi-step in silico drug design strategy, including PASS prediction, molecular docking, absorption, distribution, metabolism and excretion (ADMET) analysis, molecular dynamics simulations, frontier molecular orbitals calculations, dynamic cross-correlation matrix (DCCM), and principal component analysis (PCA). To find out the potential drug candidate against NiV target protein, more than 100 derivatives were taken from the PubChem database. After that, the Pa (probability “to be active"), and Pi (probability “to be inactive") calculation was conducted. Based on the maximum probability “to be active score (Pa), the top nine compounds were studied against NiV. Our findings suggest that the quercetin derivatives exhibit promising binding affinities with the Nipah virus phosphoprotein, particularly compounds 03 (−7.8 kcal/mol), 22 (−6.9 kcal/mol), and 89 (−7.3 kcal/mol). The molecular dynamics simulations over the 100 had confirmed excellent stability and ADMET profiles has reported that all the mentioned ligands are free from Hepatotoxicity, and AMES toxicity, suggesting them as promising candidates for anti-NiV drugs. Based on the results of molecular dynamics simulations, it was observed that the reported drug candidates 03, 22, and 89 exhibited a high degree of stability in forming protein-ligand complexes. These complexes showed only minor fluctuations in RMSF over the 100 ns simulation period. The utilization of frontier molecular orbitals aided in the understanding of the electronic structure behavior, providing strong evidence for their suitability. The study indicates that certain quercetin derivatives, such as 03, 22, and 89, show promise as potentially effective antiviral drug candidates against NiV. Future research should focus on experimental testing of these compounds to develop new antiviral drugs against NiV.

Molecular Docking and Dynamics of Xylocarpus granatum as A Potential Parkinson’s Drug Targeting Multiple Enzymes

Parkinson's disease is a global health challenge affecting over 10 million individuals worldwide, leading to increased disability-adjusted life years (DALYs) and a rise in mortality rates. This study explores the potential anti-Parkinson's properties of Xylocarpus granatum, focusing on its interaction with key enzymes associated with the disease: catechol-O-methyltransferase (COMT), adenosine A2A receptor (A2AR), and monoamine oxidase-B (MAO-B). Using molecular docking and molecular dynamics approaches with YASARA Structure, the ethanol extract of X. granatum was investigated for its mechanism of action. Among 30 compounds, five demonstrated promising binding affinities. Structural flexibility analysis revealed minimal fluctuations in active-site residues, highlighting the stability of key complexes involving kaempferol, epicatechin, epigallocatechin, and native ligands. Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) simulations provided insights into the binding energy of these complexes. Notably, kaempferol exhibited higher binding energy than the natural ligand, suggesting superior binding affinity. Analysis of the average radius of gyration (Rg) showcased control drug-MAO-B exhibited higher Rg values, indicating a more flexible protein conformation. Confirming mode stability with root mean square deviation (RMSD) analysis shows overall stability, except in the A2AR-bound complex. The study's collective findings underscore the structural stabilization of ligand-protein complexes, contributing valuable insights into the potential anti-Parkinson's properties of X. granatum. These discoveries hold promise for developing more effective therapies for Parkinson's disease and significantly contribute to the neurology field.

Analysis of the interaction of antimalarial agents with Plasmodium falciparum glutathione reductase through molecular mechanical calculations.

Malaria remains a significant global health challenge with emerging resistance to current treatments. Plasmodium falciparum glutathione reductase (PfGR) plays a critical role in the defense mechanisms of malaria parasites against oxidative stress. In this study, we investigate the potential of targeting PfGR with conventional antimalarials and dual drugs combining aminoquinoline derivatives with GR inhibitors, which reveal promising interactions between PfGR and studied drugs. The naphthoquinone Atovaquone demonstrated particularly high affinity and potential dual-mode binding with the enzyme active site and cavity. Furthermore, dual drugs exhibit enhanced binding affinity, suggesting their efficacy in inhibiting PfGR, where the aliphatic ester bond (linker) is essential for effective binding with the enzyme's active site. Overall, this research provides important insights into the interactions between antimalarial agents and PfGR and encourages further exploration of its role in the mechanisms of action of antimalarials, including dual drugs, to enhance antiparasitic efficacy. The drugs were tested as PfGR potential inhibitors via molecular docking on AutoDock 4, which was performed based on the preoptimized structures in HF/3-21G-PCM level of theory on ORCA 5. Drug-receptor systems with the most promising binding affinities were then studied with a molecular dynamic's simulation on AMBER 16. The molecular dynamics simulations were performed with a 100ns NPT ensemble employing GAFF2 forcefield in the temperature of 310K, integration time step of 2fs, and non-bond cutoff distance of 6.0Å.