A grain-like cerium oxide nanostructure: synthesis and uric acid sensing application.

Utilizing nanomaterials on the working electrode of sensors enables the fabrication of highly sensitive devices for the detection of various analytes. Herein, a facile synthesis method is used to formulate a grain-like cerium oxide (CeO2) nanostructure. The structural features and surface properties of the synthesized CeO2 nanostructure were studied, which showed that the CeO2 nanostructure exhibited grain-like morphology, good crystalline structure, and excellent vibrational properties. To evaluate the sensing properties of grain-like CeO2 nanostructure, nanomaterial slurry was prepared in butyldiglycol acetate binder. Then, the nanomaterial slurry was drop-casted onto the working electrode of the screen-printed carbon electrode (SPCE) to fabricate the CeO2-modified SPCE sensor. The sensor's electrochemical properties were analysed, which showed excellent charge-transfer behavior compared to the bare SPCE. CV-based electrochemical sensing of uric acid (UA) on a CeO2-modified SPCE sensor exhibited excellent linear performance up to 1070 µM UA. Moreover, the sensor offers good sensitivity, low detection limit, reproducibility, selectivity, and long-term stability. The CeO2-modified SPCE sensor demonstrated a promising application for UA detection in real samples, addressing the need for timely UA concentration monitoring.

Semicarbazone, thiosemicarbazone tailed isoxazoline-pyrazole: synthesis, DFT, biological and computational assessment.

Aim: A series of semicarbazone and thiosemicarbazone-tailed hybrids comprising pyrazole and acetylisoxazoline were prepared from (R)-carvone and characterized by technique spectroscopies Nuclear Magnetic Resonance (NMR), IR and High-Resolution Mass Spectrometry. Density Functional Theory (DFT) determined the structural parameters. Their cytotoxic activity was evaluated in vitro against four human cancer cell lines.Methods & results: All the studied semi and thiosemicarbazone demonstrate a promising potential as anticancer agents. The mechanism of action of these compounds involves apoptosis in HT-1080 cells, supported by an increase in the level of caspase-3/7 activity, which also arrests the cell cycle in the G0/G1 phase. Molecular docking studies were performed to establish the potential of the most active compounds 4a and 5a. ADMET analysis showed appropriate pharmacokinetic properties, allowing structure prediction for anticancer activity.

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Enriching Anticancer Drug Pipeline with Potential Inhibitors of Cyclin-Dependent Kinase-8 Identified from Natural Products.

Cyclin-dependent kinase 8 (CDK8) is highly expressed in various cancers and common complex human diseases, and an important therapeutic target for drug discovery and development. The CDK8 inhibitors are actively sought after, especially among natural products. We performed a virtual screening using the ZINC library comprising approximately 90,000 natural compounds. We applied Lipinski's rule of five, absorption, distribution, metabolism, excretion, and toxicity properties, and pan-assay interference compounds filter to eliminate promiscuous binders. Subsequently, the filtered compounds underwent molecular docking to predict their binding affinity and interactions with the CDK8 protein. Interaction analysis were carried out to elucidate the interaction mechanism of the screened hits with binding pockets of the CDK8. The ZINC02152165, ZINC04236005, and ZINC02134595 were selected with appreciable specificity and affinity with CDK8. An all-atom molecular dynamic (MD) simulation followed by essential dynamics was performed for 200 ns. Taken together, the results suggest that ZINC02152165, ZINC04236005, and ZINC02134595 can be harnessed as potential leads in therapeutic development. Moreover, the binding of the molecules brings change in protein conformation in a way that blocks the ATP-binding site of the protein, obstructing its kinase activity. These new findings from natural products offer insights into the molecular mechanisms underlying CDK8 inhibition. CDK8 was previously associated with behavioral and neurological diseases such as autism spectrum disorder, and cancers, for example, colorectal, prostate, breast, and acute myeloid leukemia. Hence, we call for further research and experimental validation, and with an eye to inform future clinical drug discovery and development in these therapeutic fields.

Investigating Pyruvate Dehydrogenase Kinase 3 Inhibitory Potential of Myricetin Using Integrated Computational and Spectroscopic Approaches.

Protein kinases are involved in various diseases and currently represent potential targets for drug discovery. These kinases play major roles in regulating the cellular machinery and control growth, homeostasis, and cell signaling. Dysregulation of kinase expression is associated with various disorders such as cancer and neurodegeneration. Pyruvate dehydrogenase kinase 3 (PDK3) is implicated in cancer therapeutics as a potential drug target. In this current study, a molecular docking exhibited a strong binding affinity of myricetin to PDK3. Further, a 100 ns all-atom molecular dynamics (MD) simulation study provided insights into the structural dynamics and stability of the PDK3-myricetin complex, revealing the formation of a stable complex with minimal structural alterations upon ligand binding. Additionally, the actual affinity was ascertained by fluorescence binding studies, and myricetin showed appreciable binding affinity to PDK3. Further, the kinase inhibition assay suggested significant inhibition of PDK3 by myricetin, revealing an excellent inhibitory potential with an IC50 value of 3.3 µM. In conclusion, this study establishes myricetin as a potent PDK3 inhibitor that can be implicated in therapeutic targeting cancer and PDK3-associated diseases. In addition, this study underscores the efficacy of myricetin as a potential lead to drug discovery and provides valuable insights into the inhibition mechanism, enabling advancements in cancer therapeutics.

Thymoquinone, artemisinin, and thymol attenuate proliferation of lung cancer cells as Sphingosine kinase 1 inhibitors.

Sphingosine-1-phosphate (S1P) formed via catalytic actions of sphingosine kinase 1 (SphK1) behaves as a pro-survival substance and activates downstream target molecules associated with various pathologies, including initiation, inflammation, and progression of cancer. Here, we aimed to investigate the SphK1 inhibitory potentials of thymoquinone (TQ), Artemisinin (AR), and Thymol (TM) for the therapeutic management of lung cancer. We implemented docking, molecular dynamics (MD) simulations, enzyme inhibition assay, and fluorescence measurement studies to estimate binding affinity and SphK1 inhibitory potential of TQ, AR, and TM. We further investigated the anti-cancer potential of these compounds on non-small cell lung cancer (NSCLC) cell lines (H1299 and A549), followed by estimation of mitochondrial ROS, mitochondrial membrane potential depolarization, and cleavage of DNA by comet assay. Enzyme activity and fluorescence binding studies suggest that TQ, AR, and TM significantly inhibit the activity of SphK1 with IC50 values of 35.52 µM, 42.81 µM, and 53.68 µM, respectively, and have an excellent binding affinity. TQ shows cytotoxic effect and anti-proliferative potentials on H1299 and A549 with an IC50 value of 27.96 µM and 54.43 µM, respectively. Detection of mitochondrial ROS and mitochondrial membrane potential depolarization shows promising TQ-induced oxidative stress on H1299 and A549 cell lines. Comet assay shows promising TQ-induced oxidative DNA damage. In conclusion, TQ, AR, and TM act as potential inhibitors for SphK1, with a strong binding affinity. In addition, the cytotoxicity of TQ is linked to oxidative stress due to mitochondrial ROS generation. Overall, our study suggests that TQ is a promising inhibitor of SphK1 targeting lung cancer therapy.

Identification of natural compounds (proanthocyanidin and rhapontin) as high-affinity inhibitors of SARS-CoV-2 Mpro and PLpro using computational strategies.

Introduction: The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets. Material and methods: We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal/mol against Mpro and ≤ -5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes. Results: Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol. Conclusions: This study's outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.

Synthesis and evaluation of pyridine-3-carboxamide analogs as effective agents against bacterial wilt in tomatoes.

This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure-activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a-i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.

Exploiting fly ash as an ecofriendly pesticide/nematicide on Abesmoschus esculuntus: Insights into soil amendment-induced antioxidant fight against nematode mediated ROS.

Conventional pest control measures, such as chemical pesticides and nematicides, have limited efficacy and raise environmental concerns, necessitating sustainable and eco-friendly alternatives for pest management. Therefore, to find a complementary eco-friendly pesticide/nematicide, this study investigated the role of fly ash (FA) in managing a notorious pest, Meloidogyne javanica and its impact on the growth and physiology of Abelmoschus esculentus. Molecular characterization using SSU and LSU rDNA gene markers confirmed the identity of Indian M. javanica as belonging to the same species. Biotic stress induced by nematode infection was significantly alleviated (P < 0.05) by FA application at a 20% w/v, regulating of ROS accumulation (44.1% reduction in superoxide anions and 39.7% reduction in hydrogen peroxide content) in the host plant. Moreover, FA enhanced antioxidant defence enzymes like superoxide dismutase (46.6%) and catalase (112%) to combat nematode induced ROS. Furthermore, the application of FA at a 20% concentration significantly improved the biomass and biochemical attributes of okra. Fly ash also upregulated the activity of the important osmo-protectant proline (11.5 µmol/g FW) to mitigate nematode stress in host cells. Suppression of disease indices like gall index and reproduction factor, combined with in-vitro experiments, revealed that FA exhibits strong nematode mortality capacity and thus can be used as a sustainable and eco-friendly control agent against root-knot nematodes.

An Electroanalytical Enzymeless α-Fe2O3-ZnO Hybrid Nanostructure-Based Sensor for Sensitive Quantification of Nitrite Ions.

Nitrite monitoring serves as a fundamental practice for protecting public health, preserving environmental quality, ensuring food safety, maintaining industrial safety standards, and optimizing agricultural practices. Although many nitrite sensing methods have been recently developed, the quantification of nitrite remains challenging due to sensitivity and selectivity limitations. In this context, we present the fabrication of enzymeless iron oxide nanoparticle-modified zinc oxide nanorod (α-Fe2O3-ZnO NR) hybrid nanostructure-based nitrite sensor fabrication. The α-Fe2O3-ZnO NR hybrid nanostructure was synthesized using a two-step hydrothermal method and characterized in detail utilizing x-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). These analyses confirm the successful synthesis of an α-Fe2O3-ZnO NR hybrid nanostructure, highlighting its morphology, purity, crystallinity, and elemental constituents. The α-Fe2O3-ZnO NR hybrid nanostructure was used to modify the SPCE (screen-printed carbon electrode) for enzymeless nitrite sensor fabrication. The voltammetric methods (i.e., cyclic voltammetry (CV) and differential pulse voltammetry (DPV)) were employed to explore the electrochemical characteristics of α-Fe2O3-ZnO NR/SPCE sensors for nitrite. Upon examination of the sensor's electrochemical behavior across a range of nitrite concentrations (0 to 500 µM), it is evident that the α-Fe2O3-ZnO NR hybrid nanostructure shows an increased response with increasing nitrite concentration. The sensor demonstrates a linear response to nitrite concentrations up to 400 µM, a remarkable sensitivity of 18.10 µA µM-1 cm-2, and a notably low detection threshold of 0.16 µM. Furthermore, its exceptional selectivity, stability, and reproducibility make it an ideal tool for accurately measuring nitrite levels in serum, yielding reliable outcomes. This advancement heralds a significant step forward in the field of environmental monitoring, offering a potent solution for the precise assessment of nitrite pollution.

Integrated spectroscopic and computational analyses unravel the molecular interaction of pesticide azinphos-methyl with bovine beta-lactoglobulin.

Organophosphorus are typically hazardous chemicals used in the pharmaceutical, agricultural, and other industries. They pose a serious risk to human life and can be fatal upon direct exposure. Hence, studying the interaction between such compounds with proteins is crucial for environmental, health, and food safety. In this study, we investigated the interaction mechanism between azinphos-methyl (AZM) and ß-lactoglobulin (BLG) at pH 7.4 using a combination of biophysical techniques. Intrinsic fluorescence investigations revealed that BLG fluorescence was quenched in the presence of increasing AZM concentrations. The quenching mechanism was identified as static, as evidenced by a decrease in the fluorescence quenching constant (1.25 × 104, 1.18 × 104, and 0.86 × 104 M-1) with an increase in temperatures. Thermodynamic calculations (ΔH > 0; ΔS > 0) affirmed the formation of a complex between AZM and BLG through hydrophobic interactions. The BLG's secondary structure was found to be increased due to AZM interaction. Ultraviolet -visible spectroscopy data showed alterations in BLG conformation in the presence of AZM. Molecular docking highlighted the significant role of hydrophobic interactions involving residues such as Val43, Ile56, Ile71, Val92, Phe105, and Met107 in the binding between BLG and AZM. A docking energy of -6.9 kcal mol-1, and binding affinity of 1.15 × 105 M-1 suggest spontaneous interaction between AZM and BLG with moderate to high affinity. These findings underscore the potential health risks associated with the entry of AZM into the food chain, emphasizing the need for further consideration of its impact on human health.

Investigation of phytochemicals isolated from selected Saudi medicinal plants as natural inhibitors of SARS CoV-2 main protease: In vitro, molecular docking and simulation analysis.

The escalation of many coronavirus variants accompanied by the lack of an effective cure has motivated the hunt for effective antiviral medicines. In this regard, 18 Saudi Arabian medicinal plants were evaluated for SARS CoV-2 main protease (Mpro) inhibition activity. Among them, Terminalia brownii and Acacia asak alcoholic extracts exhibited significant Mpro inhibition, with inhibition rates of 95.3 % and 95.2 %, respectively, at a concentration of 100 µg/mL. Bioassay-guided phytochemical study for the most active n-butanol fraction of T. brownii led to identification of eleven compounds, including two phenolic acids (1, and 2), seven hydrolysable tannins (3-10), and one flavonoid (11) as well as four flavonoids from A. asak (12-15). The structures of the isolated compounds were established using various spectroscopic techniques and comparison with known compounds. To investigate the chemical interactions between the identified compounds and the target Mpro protein, molecular docking was performed using AutoDock 4.2. The findings identified compounds 4, 5, 10, and 14 as the most potential inhibitors of Mpro with binding energies of -9.3, -8.5, -8.1, and -7.8 kcal mol-1, respectively. In order to assess the stability of the protein-ligand complexes, molecular dynamics simulations were conducted for a duration of 100 ns, and various parameters such as RMSD, RMSF, Rg, and SASA were evaluated. All selected compounds 4, 5, 10, and 14 showed considerable Mpro inhibiting activity in vitro, with compound 4 being the most powerful with an IC50 value of 1.2 µg/mL. MM-GBSA free energy calculations also revealed compound 4 as the most powerful Mpro inhibitor. None of the compounds (4, 5, 10, and 14) display any significant cytotoxic activity against A549 and HUVEC cell lines.

Exploring therapeutic potential of Rutin by investigating its cyclin-dependent kinase 6 inhibitory activity and binding affinity.

Cyclin-dependent kinase 6 (CDK6) participates in numerous signalling pathways and regulates various physiological processes. Due to its unique structural features and promising therapeutic potential, CDK6 has emerged as a drug target for designing and developing small-molecule inhibitors for anti-cancer therapeutics and other CDK6-associated diseases. The current study evaluates binding affinity and the inhibitory potential of rutin for CDK6 to develop a proof of concept for rutin as a potent CDK6 inhibitor. Molecular docking and 200 ns all-atom simulations reveal that rutin binds to the active site pocket of CDK6, forming interactions with key residues of the binding pocket. In addition, the CDK6-rutin complex remains stable throughout the simulation trajectory. A high binding constant (Ka = 7.6 × 105M-1) indicates that rutin has a strong affinity for CDK6. Isothermal titration calorimetry has further validated a strong binding of rutin with CDK6 and its spontaneous nature. The kinase activity of CDK6 is significantly inhibited by rutin with an IC50 value of 3.10 µM. Our findings highlight the significant role of rutin in developing potential therapeutic molecules to manage cancer and CDK6-associated diseases via therapeutic targeting of CDK6.

Harnessing memantine in Alzheimer's disease therapy through inhibition of microtubule affinity-regulating kinase: Mechanistic insights.

Alzheimer's disease (AD) is one of the neurodegenerative disorder that primarily affects memory, thinking, and behavior, eventually leading to severe cognitive impairment. Therapeutic management of AD is urgently needed to improve the quality and lifestyle of patients. Tau phosphorylating kinases are considered attractive therapeutic targets. Microtubule affinity-regulating kinase 4 (MARK4) is directly linked with pathological phosphorylations of tau, highlighting its role in the therapeutic targeting of AD. The current manuscript shows the MARK4 inhibitory effect of Memantine (MEM), a drug used in treating AD. We have performed fluorescence based binding measurements, enzyme inhibition assay, docking and molecular dynamics (MD) simulations to understand the binding of of MARK4 and MEM and subsequent inhibition in the kinase activity. A 100 ns MD simulations provided a detailed analysis of MARK4-MEM complex and the role of potential critical residues in the binding. Finally, this study provides molecular insights into the therapeutic implication of MEM in AD therapeutics. We propose MEM effectively inhibits MARK4, it may be implicated in the development of targeted and efficient treatments for AD.

Probing the interaction mechanisms between sunset yellow dye and trypsin protein leading to amorphous aggregation under low pH conditions.

Protein aggregation poses a significant concern in the field of food sciences, and various factors, such as synthetic food dyes, can contribute to protein aggregation. One such dye, Sunset Yellow (SY), is commonly employed in the food industry. Trypsin was used as a model protein to assess the impact of SY. We employed several biophysical techniques to examine the binding and aggregation mechanisms between SY and trypsin at different pHs. Results from intrinsic fluorescence measurements indicate a stronger interaction between SY and trypsin at pH 2.0 compared to pH 6.0. Turbidity data reveal trypsin aggregation in the presence of 0.05-3.0 mM SY at pH 2.0, while no aggregation was observed at pH 6.0. Kinetic data demonstrate a rapid, lag-phase-free SY-induced aggregation of trypsin. Circular dichroism analysis reveals that trypsin adopts a secondary structure in the presence of SY at pH 6.0, whereas at pH 2.0, the secondary structure was nearly lost with increasing SY concentrations. Furthermore, turbidity and kinetics data suggest that trypsin aggregation depends on trypsin concentrations and pH. Our study highlights potential health risks associated with the consumption of SY, providing insights into its impact on human health and emphasizing the necessity for further research in this field.

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors.

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as a stand-alone multistage signalling regulator of P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a 'click' reaction. The selected CQTrICh-analogs: 7l and 7r inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of Plasmodium falciparum, with IC50 values of 2.4 µM & 1.8 µM (7l), and 3.5 µM & 2.7 µM (7r), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. 7l and 7r were found to stably interact with the catalytically active ATP-binding pocket of PfCDPK1 via energetically favourable H-bonds. The interaction was confirmed in vitro by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with PfCDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.

Identification of High-Affinity Inhibitors of TANK-Binding Kinase 1 (TBK1): A Promising Frontier for Controlling Inflammatory Signaling in Cancer.

BACKGROUND: TANK-binding kinase 1 (TBK1) is an important serine/threonine kinase involved in inflammatory signaling pathways, influencing cellular processes such as proliferation, programmed cell death, autophagy, and immune response regulation. Dysregulation of TBK1 has been linked to cancer progression and neurodegenerative disorders, making it an attractive target for therapeutic development. This study aimed to identify potential TBK1 inhibitors using a structure-based virtual screening approach. METHODS: We conducted a comprehensive screening of the ZINC database to identify compounds with high binding affinity for TBK1, employing molecular docking as the primary selection criterion. The top candidates were then subjected to extensive 200 ns molecular dynamics (MD) simulations to assess the conformational dynamics of TBK1 and the stability of the protein-ligand complexes, with a focus on ZINC02095133 and ZINC02130647. RESULTS: The findings revealed that TBK1 forms stable complexes with ZINC02095133 and ZINC02130647, demonstrating consistent interactions throughout the MD simulations. This suggests that these compounds hold promise as potential lead molecules for future therapies targeting TBK1. CONCLUSIONS: This study identifies ZINC02095133 and ZINC02130647 as promising TBK1 inhibitors with therapeutic potential. However, further experimental validation and optimization are required to develop novel inhibitors for diseased conditions associated with TBK1 signaling. These findings pave the way for future investigations into the clinical utility of these compounds in combating TBK1-related pathologies.

Investigating the role of thymol as a promising inhibitor of pyruvate dehydrogenase kinase 3 for targeted cancer therapy.

Protein kinases have emerged as major contributors to various diseases. They are currently exploited as a potential target in drug discovery because they play crucial roles in cell signaling, growth, and regulation. Their dysregulation is associated with inflammatory disorders, cancer, and neurodegenerative diseases. Pyruvate dehydrogenase kinase 3 (PDK3) has become an attractive drug target in cancer therapeutics. In the present study, we investigated the effective role of thymol in PDK3 inhibition due to the high affinity predicted through molecular docking studies. Hence, to better understand this inhibition mechanism, we carried out a 100 ns molecular dynamics (MD) simulation to analyse the dynamics and stability of the PDK3-thymol complex. The PDK3-thymol complex was stable and energetically favourable, with many intramolecular hydrogen bond interactions in the PDK3-thymol complex. Enzyme inhibition assay showed significant inhibition of PDK3 by thymol, revealing potential inhibitory action of thymol towards PDK3 (IC50 = 2.66 µM). In summary, we established thymol as one of the potential inhibitors of PDK3, proposing promising therapeutic implications for severe diseases associated with PDK3 dysregulation. This study further advances our understanding of thymol's therapeutic capabilities and potential role in cancer treatment.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates.

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

An integrated docking and molecular dynamics simulation approach to discover potential inhibitors of activin receptor-like kinase 1.

Activin receptor-like kinase 1 (ALK1) is a transmembrane receptor involved in crucial signaling pathways associated with angiogenesis and vascular development. Inhibition of ALK1 signaling has emerged as a promising therapeutic strategy for various angiogenesis-related diseases, including cancer and hereditary hemorrhagic telangiectasia. This study aimed to investigate the potential of phytoconstituents as inhibitors of ALK1 using a combined approach of virtual screening and molecular dynamics (MDs) simulations. Phytoconstituents from the IMPPAT 2.0 database underwent virtual screening to identify potential inhibitors of ALK1. The compounds were initially filtered based on physicochemical parameters, following Lipinski's rules and the PAINS filter. Subsequently, compounds demonstrating high binding affinities in docking analysis were further analyzed. Additional assessments, including ADMET, PAINS, and PASS evaluations, were conducted to identify more potent hits. Through interaction analysis, a phytoconstituent, Candidine, exhibited appreciable affinity and specific interactions with the ALK1 active site. To validate the results, MD simulations and principal components analysis were performed. The MD simulations demonstrated that Candidine stabilized the ALK1 structure and reduced conformational fluctuations. In conclusion, Candidine shows promising potential as binding partners of ALK1. These findings provide a foundation for further exploration and development of Candidine as a lead molecule for therapeutic interventions targeting ALK1-associated diseases.

Computational investigation of the impact of potential AT2R polymorphism on small molecule binding.

For more than a century, the renin-angiotensin system (RAS) has been acknowledged for playing a crucial part in the physiological control of arterial pressure, as well as sodium and fluid balance. It is now generally acknowledged that one of the receptor of RAS system i.e. angiotensin type 2 receptor (AT2R) functions as a repair system during pathophysiologic circumstances and performs a significant protective role. Efforts have been made previously to design suitable agonist and antagonist molecules to potentially modulate AT2R. One of the agonists and antagonists, named C21 and EMA401, has been studied in a number of pathological conditions. Additionally, a wide panel of single nucleotide polymorphisms (SNPs) has been reported for AT2R, which might potentially affect the efficacy of these molecules. Therefore, computational investigations have been carried out to analyze all the SNPs (1151) reported in NCBI to find potential SNPs affecting the active site of AT2R, as this domain is still unexplored. Structures of these polymorphic forms were modeled, and in silico drug interaction studies with C21 and EMA401 were carried out. The two mutants (rs868939201 and rs1042852794) that significantly affect the binding affinity as that of the wild type were subjected to molecular dynamics simulations. Our analysis of native and mutant AT2R and their complexes with C21 and EMA401 indicated that the occurrence of these mutations affects the conformation of the protein and has affected the binding of these ligand molecules. The study's findings will aid in the development of better, more versatile medications in the near future, and also in vitro and in vivo studies might be planned in accordance with recent findings.Communicated by Ramaswamy H. Sarma.