Zingiberaceae-derived phytomolecules inhibit Japanese encephalitis virus RNA dependent RNA polymerase: a molecular dynamics study.

The Japanese encephalitis virus, (JEV), is a flavivirus mostly transmitted by Culex mosquitoes mostly present in Southeast Asia and the Western Pacific region. Ardeid-wading birds are the natural reservoir of JEV; nonetheless, pigs are frequently a key amplifying host during epidemics in human populations. Although more domestic animals and wildlife are JEV hosts, it is unclear how these animals fit into the ecology and epidemiology of the virus. Even though there is no specific therapy, vaccines are available to prevent this infection. However, current vaccinations do not work against every clinical isolate and can cause neurological problems in certain people. In this study, we have screened 501 phytochemical compounds from various plants from the Zingeberaceae family against the RdRp protein of JEV. Based on this, the top five compounds (IMPHY014466, IMPHY004928, IMPHY007097, IMPHY014179 and IMPHY005010) were selected based on the obtained docking scores, which was above -8.0 Kcal/mol. Further, the binding affinity of these selected ligands was also analysed using molecular interaction, and the presence of interactions like hydrogen bonds, hydrophobic bonds and polar bonds with respective active residues were identified and studied elaborately. Furthermore, the dynamic stability of the docked RdRp protein with these selected phytochemicals was studied using Molecular dynamic simulation and essential dynamics. The free energy landscape analysis also provided information about the energy transition responsible stability of the complex. The results obtained advocated phytochemical compounds from the zingeberaceae family for future experimental validation, as these compounds exhibited significant potential as JEV antagonists.Communicated by Ramaswamy H. Sarma.

Exploring the promising potential of noscapine for cancer and neurodegenerative disease therapy through inhibition of integrin-linked kinase-1.

Integrin-linked kinase (ILK), a ß1-integrin cytoplasmic domain interacting protein, supports multi-protein complex formation. ILK-1 is involved in neurodegenerative diseases by promoting neuro-inflammation. On the other hand, its overexpression induces epithelial-mesenchymal transition (EMT), which is a major hallmark of cancer and activates various factors associated with a tumorigenic phenotype. Thus, ILK-1 is considered as an attractive therapeutic target. We investigated the binding affinity and ILK-1 inhibitory potential of noscapine (NP) using spectroscopic and docking approaches followed by enzyme inhibition activity. A strong binding affinity of NP was measured for the ILK-1 with estimated Ksv (M-1) values of 1.9 × 105, 3.6 × 105, and 4.0 × 105 and ∆G0 values (kcal/mol) -6.19554, -7.8557 and -8.51976 at 298 K, 303 K, and 305 K, respectively. NP binds to ILK-1 with a docking score of -6.6 kcal/mol and forms strong interactions with active-site pocket residues (Lys220, Arg323, and Asp339). The binding constant for the interaction of NP to ILK-1 was 1.04 × 105 M-1, suggesting strong affinity and excellent ILK-1 inhibitory potential (IC50 of ∼5.23µM). Conformational dynamics of ILK-1 were also studied in the presence of NP. We propose that NP presumably inhibits ILK-1-mediated phosphorylation of various downstream signalling pathways that are involved in cancer cell survival and neuroinflammation.

Optimized Ribociclib nanostructured lipid carrier for the amelioration of skin cancer: Inferences from ex-vivo skin permeation and dermatokinetic studies.

Current research focuses on explicitly developing and evaluating nanostructured lipidic carriers (NLCs) for the chemotherapeutic drug Ribociclib (RCB) via the topical route to surmount the inherent bioavailability shortcomings. The absolute oral bioavailability has not been determined, but using a physiologically based pharmacokinetic model it was predicted that 65.8 % of the standard dose of RCB (600 mg) would be absorbed mainly in the small intestine. RCB-NLCs were produced using the solvent evaporation method, and Box-Behnken Design (BBD) was employed to optimize composition. The prepared NLCs had an average PS of 79.29 ± 3.53 nm, PDI of 0.242 ± 0.021, and a %EE of 86.07 ± 3.14. The TEM analysis disclosed the spherical form and non-aggregative nature of the NLCs. The outcomes of an in-vitro release investigation presented cumulative drug release of 84.97 ± 3.37 % in 24 h, significantly higher than that from the RCB suspension (RCB-SUS). Ex-vivo skin permeation investigations on rodent (Swiss albino mice) revealed that RCB-NLCs have 1.91 times increases in skin permeability comparable to RCB-SUS. Compared to RCB-SUS, RCB-NLCs were able to penetrate deeper into the epidermis membrane than RCB-SUS as per the findings of confocal microscopy. In dermatokinetic study, higher amount of RCB was maintained in both the layers of mice's skin when treated with RCB-NLCs gel comparable to the RCB-SUS gel preparation. The in-vitro, ex-vivo, CLSM, and dermatokinetics data demonstrated a significant possibility for this novel RCB formulation to be effective against skin cancer.

Investigating the effects of four medicinal plants against dengue virus through QSAR modeling and molecular dynamics studies.

The Dengue virus (DENV) has been increasingly recognized as a prevalent viral pathogen responsible for global transmission of infection. It has been established that DENV's NS5 methyltransferase (MTase) controls viral replication. As a result, NS5 MTase is considered a potentially useful drug target for DENV. In this study, the two phases of virtual screening were conducted using the ML-based QSAR model and molecular docking to identify potential compounds against NS5 of DENV. Four medicinal plants [Aloe vera, Cannabis sativa (Hemp), Ocimum sanctum (Holy Basil; Tulsi), and Zingiber officinale (Ginger)] that showed anti-viral properties were selected for sourcing the phytochemicals and screening them against NS5. Additionally, re-docking at higher exhaustiveness and interaction analysis were performed which resulted in the identification of the top four hits (135398658, 5281675, 119394, and 969516) which showed comparable results with the control Sinefungin (SFG). Post molecular dynamics simulation, 135398658 showed the lowest RMSD (0.4-0.5 nm) and the maximum number of hydrogen bonds (eight hydrogen bonds) after the control while 5281675 and 969516 showed comparable hydrogen bonds to the control. These compounds showed direct interactions with the catalytic site residues GLU111 and ASP131, in addition to this these compounds showed stable complex formation as depicted by principal component analysis and free energy landscape. 135398658 showed lower total binding free energy (ΔGTotal = -36.56 kcal/mol) than the control, while 5281675 had comparable values to the control (ΔGTotal = -34.1 kcal/mol). Overall, the purpose of this study was to identify phytochemicals that inhibit NS5 function, that could be further tested experimentally to treat dengue virus (DENV).Communicated by Ramaswamy H. Sarma.

Identification of mitogen-activated protein kinase 7 inhibitors from natural products: Combined virtual screening and dynamic simulation studies.

Mitogen-activated protein kinase 7 (MAPK7) is a serine/threonine protein kinase that belongs to the MAPK family and plays a vital role in various cellular processes such as cell proliferation, differentiation, gene transcription, apoptosis, metabolism, and cell survival. The elevated expression of MAPK7 has been associated with the onset and progression of multiple aggressive tumors in humans, underscoring the potential of targeting MAPK7 pathways in therapeutic research. This pursuit holds promise for the advancement of anticancer drug development by developing potential MAPK7 inhibitors. To look for potential MAPK7 inhibitors, we exploited structure-based virtual screening of natural products from the ZINC database. First, the Lipinski rule of five criteria was used to filter a large library of ~90,000 natural compounds, followed by ADMET and pan-assay interference compounds (PAINS) filters. Then, top hits were chosen based on their strong binding affinity as determined by molecular docking. Further, interaction analysis was performed to find effective and specific compounds that can precisely bind to the binding pocket of MAPK7. Consequently, two compounds, ZINC12296700 and ZINC02123081, exhibited significant binding affinity and demonstrated excellent drug-like properties. All-atom molecular dynamics simulations for 200 ns confirmed the stability of MAPK7-ZINC12296700 and MAPK7-ZINC02123081 docked complexes. According to the molecular mechanics Poisson-Boltzmann surface area investigation, the binding affinities of both complexes were considerable. Overall, the result suggests that ZINC12296700 and ZINC02123081 might be used as promising leads to develop novel MAPK7 inhibitors. Since these compounds would interfere with the kinase activity of MAPK7, therefore, may be implemented to control cell growth and proliferation in cancer after required validations.

Identification of potential Escherichia coli DNA gyrase B inhibitors targeting antibacterial therapy: an integrated docking and molecular dynamics simulation study.

The alarming rise in the rate of antibiotic resistance is a matter of significant concern. DNA gyrase B (GyrB), a critical bacterial enzyme involved in DNA replication, transcription, and recombination, has emerged as a promising target for antibacterial agents. Inhibition of GyrB disrupts bacterial DNA replication, leading to cell death, making it an attractive candidate for antibiotic development. Although several classes of antibiotics targeting GyrB are currently in clinical use, the emergence of antibiotic resistance necessitates the exploration of novel inhibitors. In this study, we aimed to identify potential Escherichia coli GyrB inhibitors from a database of phytoconstituents sourced from Indian medicinal plants. Utilizing virtual screening, we performed a rigorous search to identify compounds with the most promising inhibitory properties against GyrB. Two compounds, namely Zizogenin and Cucurbitacin S, were identified based on their favorable drug likeliness and pharmacokinetic profiles. Employing advanced computational techniques, we analyzed the binding interactions of Zizogenin and Cucurbitacin S with the ATP-binding site of GyrB through molecular docking simulations. Both compounds exhibited robust binding interactions, evidenced by their high docking energy scores. To assess the stability of these interactions, we conducted extensive 100 ns molecular dynamics (MD) simulations, which confirmed the stability of Zizogenin and Cucurbitacin S when bound to GyrB. In conclusion, our study highlights Zizogenin and Cucurbitacin S as promising candidates for potential antibacterial agents targeting GyrB. Experimental validation of these compounds is warranted to further explore their efficacy and potential as novel antibiotics to combat antibiotic-resistant bacteria.Communicated by Ramaswamy H. Sarma.

Aegle marvels (L.) Correa Leaf Essential Oil and Its Phytoconstituents as an Anticancer and Anti-Streptococcus mutans Agent.

Aegle mamelons (A. marmelos) or Indian Bael leaves possess anti-cancerous and antibacterial properties and are used in the traditional medicine system for the treatment of oral infections. In the present study, the essential oil of the leaves of A. marmelos was explored for its anticancer, antioxidant, and anti-cariogenic properties. The hydro-distilled oil of A. marmelos leaves was analyzed using gas chromatography coupled with mass spectrometry (GC-MS). Monoterpene limonene (63.71%) was found to have the highest percentage after trans-2-Hydroxy-1,8-cineole and p-Menth-2,8-dien-1-ol. The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was used to investigate the anticancer activity of the extracted oil against human oral epidermal carcinoma (KB), and the results showed significantly higher (**** p < 0.0001) anticancer activity (45.89%) in the doxorubicin (47.87%) when compared to the normal control. The antioxidant activity of the essential oil was evaluated using methods of DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)). The results showed a significant (*** p < 0.001) percentage of inhibition of DPPH-induced free radical (70.02 ± 1.6%) and ABTS-induced free radical (70.7 ± 1.32%) at 100 µg/mL with IC50, 72.51 and 67.33 µg/mL, respectively, comparatively lower than standard compound ascorbic acid. The results of the molecular docking study of the significant compound limonene with the receptors tyrosinase and tyrosine kinase 2 supported the in vitro antioxidant potential. The anti-cariogenic activity was evaluated against Streptococcus mutans (S. mutans). Results showed a significant minimum inhibitor concentration of 0.25 mg/mL and the killing time was achieved at 3 to 6 h. The molecular-docking study showed that limonene inhibits the surface receptors of the S. mutans c-terminal domain and CviR protein. The study found that A. marmelos leaves have potential anti-carcinoma, antioxidant, and anti-cariogenic effects on human oral epidermal health, making them a valuable natural therapeutic agent for managing oral cancer and infections.

Ex Vivo Antiplatelet and Thrombolytic Activity of Bioactive Fractions from the New-Fangled Stem Buds of Ficus religiosa L. with Simultaneous GC-MS Examination.

Different parts of Ficus religiosa are the common components of various traditional formulations for the treatment of several blood disorders. The new-fangled stem buds' powder was extracted with 80% ethanol and successively fractionated by chloroform and methanol. Chloroform and methanol fractions of Ficus religiosa (CFFR and MFFR) were tested for antiplatelet, antithrombotic, thrombolytic, and antioxidant activity in ex vivo mode. The MFFR was particularly investigated for GC-MS and toxicity. The antiplatelet activity of the CFFR, MFFR, and standard drug aspirin at 50 µg/mL was 54.32%, 86.61%, and 87.57%, and a significant delay in clot formation was noted. CFFR at different concentrations did not show a significant effect on the delay of clot formation, antiplatelet, and free radical scavenging activity. The most possible marker compounds for antiplatelet and antioxidant activity identified by GC-MS in the MFFR are salicylate derivatives aromatic compounds such as benzeneacetaldehyde (7), phenylmalonic acid (13), and Salicylic acid (14), as well as Benzamides derivatives such as carbobenzyloxy-dl-norvaline (17), 3-acetoxy-2(1H)-pyridone (16), and 3-benzylhexahydropyrrolo [1,2-a] pyrazine-1,4-dione (35). A toxicity study of MFFR did not show any physical indications of toxicity and mortality up to 1500 mg/kg body weight and nontoxic up to 1000 mg/kg, which is promising for the treatment of atherothrombotic diseases.

Formulation Development, Optimization by Box-Behnken Design, and In Vitro and Ex Vivo Characterization of Hexatriacontane-Loaded Transethosomal Gel for Antimicrobial Treatment for Skin Infections.

There are many different infections and factors that can lead to skin illnesses, but bacteria and fungi are the most frequent. The goal of this study was to develop a hexatriacontane-loaded transethosome (HTC-TES) for treating skin conditions caused by microbes. The HTC-TES was developed utilizing the rotary evaporator technique, and Box-Behnken design (BBD) was utilized to improve it. The responses chosen were particle size (nm) (Y1), polydispersity index (PDI) (Y2), and entrapment efficiency (Y3), while the independent variables chosen were lipoid (mg) (A), ethanol (%) (B), and sodium cholate (mg) (C). The optimized TES formulation with code F1, which contains lipoid (mg) (A) 90, ethanol (%) (B) 25, and sodium cholate (mg) (C) 10, was chosen. Furthermore, the generated HTC-TES was used for research on confocal laser scanning microscopy (CLSM), dermatokinetics, and in vitro HTC release. The results of the study reveal that the ideal formulation of the HTC-loaded TES had the following characteristics: 183.9 nm, 0.262 mV, -26.61 mV, and 87.79% particle size, PDI, and entrapment efficiency, respectively. An in vitro study on HTC release found that the rates of HTC release for HTC-TES and conventional HTC suspension were 74.67 ± 0.22 and 38.75 ± 0.23, respectively. The release of hexatriacontane from TES fit the Higuchi model the best, and the Korsmeyer-Peppas model indicates the release of HTC followed a non-Fickian diffusion. By having a higher negative value for cohesiveness, the produced gel formulation demonstrated its stiffness, whereas good spreadability indicated better gel application to the surface. In a dermatokinetics study, it was discovered that TES gel considerably increased HTC transport in the epidermal layers (p < 0.05) when compared to HTC conventional formulation gel (HTC-CFG). The CLSM of rat skin treated with the rhodamine B-loaded TES formulation demonstrated a deeper penetration of 30.0 µm in comparison to the hydroalcoholic rhodamine B solution (0.15 µm). The HTC-loaded transethosome was determined to be an effective inhibitor of pathogenic bacterial growth (S. aureus and E. coli) at a concentration of 10 mg/mL. It was discovered that both pathogenic strains were susceptible to free HTC. According to the findings, HTC-TES gel can be employed to enhance therapeutic outcomes through antimicrobial activity.

Preparation and Evaluation of Nanoemulsion of Citronella Essential Oil with Improved Antimicrobial and Anti-Cancer Properties.

The development of new pharmaceutical solutions for treating various diseases results from a growing understanding of the benefits of using essential oils. One of the most often used volatile materials among essential oils is the oil of the citronella plant, termed citronella essential oil (CITEO), which has potential for use in food and medicine. Its wide use is limited due to lipophilicity, high volatility and poor physicochemical stability. With this background, the present study aims to evaluate the properties of CITEO-nanoemulsion (CITEO-NE) by analyzing its antimicrobial activities against Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) and its anticancer activity against, human skin adenocarcinoma cell line (A431). The CITEO-NE was prepared and evaluated for the size range of 130 ± 5 nm, polydispersity index (PDI) of 0.127 and zeta potential -12.6 mV. The percentage % of entrapment efficiency (%EE) of nanoemulsions loaded with CIT was very high at the beginning of the study, at 95.5 ± 4.775%. The MIC was observed to be 500 µg/mL for CITEO and 250 µg/mL for CITEO-NE against S. aureus and 250 µg/mL for CITEO and 125 µg/mL for CITEO-NE against C. albicans. The time-kill assay also suggests the effectiveness of CITEO-NE against the test pathogens as a novel alternative therapy. The IC50 values of CITEO and CITEO-NE exhibited significant cytotoxic properties against the A431 cell line, with 41.20 µg/mL and 37.71 µg/mL, respectively. Hence, our findings revealed that encapsulation of CITEO increased the pharmacological properties.

Formulation, In Vitro and In Silico Evaluations of Anise (Pimpinella anisum L.) Essential Oil Emulgel with Improved Antimicrobial Effects.

Over the past decade, researchers have made several efforts to develop gel-based formulations that provide an alternative to traditional hydrogels and emulgel. Due to its excellent antibacterial properties, anise, the main constituent of Pimpinella anisum L., widely used in pharmaceuticals, was selected as the active ingredient in this study. Since many bacteria have developed considerable antibiotic resistance, this research aimed to develop an herbal emulgel for treating skin infections caused by bacteria. Given these obstacles, we developed and evaluated a new, cost-effective topical emulgel solution containing anise essential oil against Escherichia coli (E. coli). Anise-based emulgels, potential drug delivery platforms, have been evaluated for various parameters, including physical properties, viscosity, pH, rheology, encapsulation efficiency, and in vitro release research. The AEOs emulgel demonstrated remarkable colloidal stability, with a zeta potential of 29 mV, a size of 149.05 nm, and considerable polydispersity. The efficacy of anise-loaded emulgels as antibacterial formulations was evaluated in vitro. E. coli was used as a model microbial organism for the antibacterial study. Human keratinocytes (HaCaT) were used to examine the biocompatibility of the emulgel. Molecular docking revealed that the essential oil components of Pimpinella anisum L. possess a high affinity for the bacterial adhesin protein FimH of E. coli. These findings indicate that the developed AEOs have the potential to be analyzed using E. coli as a model organism.

Composition, Antibacterial Efficacy, and Anticancer Activity of Essential Oil Extracted from Psidium guajava (L.) Leaves.

Essential oils (EO) are used as a natural remedy to treat various chronic diseases, although clinical evidence is lacking. In this context, we have endeavored to measure the percentage of chemical composition and biological efficacy of Psidium guajava (guava) leaf essential oil in treating oral infections and oral cancer. The essential oil obtained from hydrodistillation of P. guajava L. leaves was analyzed by gas chromatography−mass spectrometry (GC−MS). The activities of selected oral pathogens Candida albicans (C. albicans) and Streptococcus mutans (S. mutants) were studied in vitro and in silico. MTT assay was used to test for anticancer activity against human oral epidermal carcinoma (KB). GC−MS showed that the main components of PGLEO were limonene (38.01%) and ß-caryophyllene (27.98%). Minimum inhibitory concentrations (MICs) of 0.05−0.1% were demonstrated against C. albicans and S. mutans. Antimicrobial activity against C. albicans and S. mutans, as shown by molecular linkage analysis, revealed that the main metabolites, limonene and ß-caryophyllene, potentially inhibited the receptors of C. albicans and S. mutans. PGLEO showed significant (p < 0.001) anticancer activity (45.89%) at 200 µg/mL compared to doxorubicin (47.87%) with an IC50 value of 188.98 µg/mL. The outcomes of the present study suggest that PGLEO has promising antimicrobial and anticancer activities and could be a useful source for developing a natural therapeutic agent for oral infections and oral cancer.

A review on cyclin-dependent kinase 5: An emerging drug target for neurodegenerative diseases.

Cyclin-dependent kinase 5 (CDK5) is the serine/threonine-directed kinase mainly found in the brain and plays a significant role in developing the central nervous system. Recent evidence suggests that CDK5 is activated by specific cyclins regulating its expression and activity. P35 and p39 activate CDK5, and their proteolytic degradation produces p25 and p29, which are stable products involved in the hyperphosphorylation of tau protein, a significant hallmark of various neurological diseases. Numerous high-affinity inhibitors of CDK5 have been designed, and some are marketed drugs. Roscovitine, like other drugs, is being used to minimize neurological symptoms. Here, we performed an extensive literature analysis to highlight the role of CDK5 in neurons, synaptic plasticity, DNA damage repair, cell cycle, etc. We have investigated the structural features of CDK5, and their binding mode with the designed inhibitors is discussed in detail to develop attractive strategies in the therapeutic targeting of CDK5 for neurodegenerative diseases. This review provides deeper mechanistic insights into the therapeutic potential of CDK5 inhibitors and their implications in the clinical management of neurodegenerative diseases.

Solubility Enhancement, Formulation Development, and Antibacterial Activity of Xanthan-Gum-Stabilized Colloidal Gold Nanogel of Hesperidin against Proteus vulgaris.

The objective of the study was to develop a transdermal nanoformulation of hesperidin (HSP) against Proteus vulgaris (P. vulgaris). Based on the low water solubility of HSP, we prepared HSP-enabled AuNPs stabilized with xanthan gum (XA), referred to as HSP@XA@AuNPs. The HSP@XA@AuNP formulation was evaluated for particle size (43.16 nm), PDI (0.565), zeta potential (-31.9 mV), and entrapment efficiency (56.7%). The HSP@XA@AuNPs gel was developed by incorporating selected formulation grades into a 1% Carbopol gel base and characterized by physical evaluation and rheological studies. The color of the HSP@XA@AuNP gel was light pink, and the texture was very smooth and non-greasy. The gel was shown to be odorless. A field emission scanning electron microscope (FESEM) was used to investigate the shape of HSP@XA@AuNPs further. The drug release was 73.08% for the HSP@XA@AuNPs and 86.26% for the HSP@XA@AuNPs gel in 500 min. The prepared gel showed antimicrobial activity against P. vulgaris with an MIC of 1.78 µg/mL. In conclusion, the HSP@XA@AuNPs gel could be an advanced modality for treating P. vulgaris.

Vancomycin as an Antibacterial Agent Capped with Silver Nanoparticles: An Experimental Potential Analysis.

For the treatment of various infections, a variety of antimicrobial drugs are formulated. Nevertheless, many bacterial infections now exhibit antibiotic resistance due to the widespread utilization antibiotics. Methicillin-resistant among the most dangerous multidrug-resistant bacteria is Staphylococcus aureus (MRSA). Vancomycin became a viable therapy option due to MRSA resistance to methicillin medicines. One of the well-informed antibacterial compounds with wideband antibacterial activity is silver nanoparticles (AgNPs). AgNPs are thus suitable candidates for usage in conjunction alongside vancomycin to increase its antibacterial effect. The goal of the present research work is to boost the antibacterial potency of the glycopeptide antibiotic vancomycin towards Gram-positive (Staphylococcus aureus) but also Gram-negative (Escherichia coli) bacteria. The chemical reduction approach is used to create a colloidal solution of silver nanoparticles utilizing silver nitrate as a precursor in the environment of the ionic surfactant trisodium citrate that serves as covering including reducing reagent. Vancomycin was used to functionalize the synthesized nanoparticles and create the nanodrug complex (Van@AgNPs). The synergistic antibacterial potential of silver nanoparticles coated with vancomycin on both test pathogens was investigated using the agar well diffusion technique. The antibacterial potency for both classes of bacteria has significantly increased, according to the well diffusion test. It has been noted that this improvement is synergistic instead of additive.

Identification of 11-Hydroxytephrosin and Torosaflavone A as Potential Inhibitors of 3-Phosphoinositide-Dependent Protein Kinase 1 (PDPK1): Toward Anticancer Drug Discovery.

The 3-phosphoinositide-dependent protein kinase 1 (PDPK1) has a significant role in cancer progression and metastasis as well as other inflammatory disorders, and has been proposed as a promising therapeutic target for several malignancies. In this work, we conducted a systematic virtual screening of natural compounds from the IMPPAT database to identify possible PDPK1 inhibitors. Primarily, the Lipinski rules, ADMET, and PAINS filter were applied and then the binding affinities, docking scores, and selectivity were carried out to find effective hits against PDPK1. Finally, we identified two natural compounds, 11-Hydroxytephrosin and Torosaflavone A, bearing substantial affinity with PDPK1. Both compounds showed drug-likeness as predicted by the ADMET analysis and their physicochemical parameters. These compounds preferentially bind to the ATP-binding pocket of PDPK1 and interact with functionally significant residues. The conformational dynamics and complex stability of PDPK1 with the selected compounds were then studied using interaction analysis and molecular dynamics (MD) simulations for 100 ns. The simulation results revealed that PDPK1 forms stable docked complexes with the elucidated compounds. The findings show that the newly discovered 11-Hydroxytephrosin and Torosaflavone A bind to PDPK1 in an ATP-competitive manner, suggesting that they could one day be used as therapeutic scaffolds against PDPK1-associated diseases including cancer.

Discovery, Development, Inventions and Patent Review of Fexinidazole: The First All-Oral Therapy for Human African Trypanosomiasis.

Human African trypanosomiasis (HAT or 'sleeping sickness') is a neglected tropical disease. If untreated, it is always fatal and leads to death. A few treatments are available for HAT, but most of them require a skilled professional, which increases the financial burden on the patient. Recently, fexinidazole (FEX) has been approved by the European Medicine Agency (EMA) and the United States Food and Drug Administration (USFDA) as the first all-oral therapy for the treatment of stage-1 (hemolymphatic) as well as stage-2 (meningoencephalitic) of HAT. Before the FEX approval, there were separate treatments for stage-1 and stage-2 of HAT. This study reviews the discovery, development timeline, inventions, and patent literature of FEX. It was first approved by EMA and USFDA in 2018 and 2021, respectively. FEX was also added to the World Health Organization's list of essential drugs in 2019. The patent literature search revealed many types of patents/patent applications (compound, salt, process, method of treatment, drug combinations, and compositions) related to FEX, which have been summarized in this article. The authors foresee a great scope to develop more inventions based on FEX (novel salts, polymorphs, drug conjugates, cyclodextrin complex, etc.) for the treatment of many protozoal diseases (Leishmaniasis and Chagas disease), inflammatory diseases, and other microbial infections. New combinations of FEX with other treatments of HAT may also provide fruitful results. This review might be useful to the scientists working on the HAT and other neglected diseases to develop novel inventions and innovations of therapeutic relevance.

Interleukin-6 expression and its modulation by diacerein in a rat model of chronic stress induced cardiac dysfunction.

People with chronic stress have higher levels of pro-inflammatory cytokines, which enhance their susceptibility to cardiovascular diseases. Diacerein has ability to modulate pro-inflammatory cytokines such as IL-1ß and IL-6; however, its efficacy in chronic stress associated cardiovascular diseases is not yet assessed. In this study, we standardized a rat model of chronic unpredictable stress (CUS) demonstrating cardiovascular dysfunctions and further assessed the effect of IL-6 modulator, diacerein, on cardiovascular functions in CUS exposed rats. The CUS procedure consisted of exposing male albino Wistar rats to random stressors, everyday for 8 weeks. The binding affinity of diacerein with IL-6 was ascertained using Docking tools viz AutoDock and SwissDock. Moreover, diacerein was administered (50 mg/kg/day x 20 days P.O) post CUS exposure to rats and the serum IL-6 levels and heart functions of CUS rats were determined by ELISA and ECG-HRV analysis, respectively. 8 weeks of CUS exposure resulted in two-fold increase in serum corticosterone and IL-6 levels in rats. The ECG and HRV analysis of CUS rats showed altered sinus rhythm, elevated heart rate, systolic blood pressure and sympathetic tone. Molecular docking studies revealed diacerein high binding affinity towards IL-6 receptor. The post-treatment of diacerein in CUS rats prevented these cardiovascular dysfunctions. Our findings thus suggests that IL-6 may have a prominent role in chronic stress induced cardiovascular dysfunctions and diacerein, could be used as a preventive measure for such conditions.

Identification of 3-((1-(Benzyl(2-hydroxy-2-phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrazine-2-carboxylic Acid as a Potential Inhibitor of Non-Nucleosidase Reverse Transcriptase Inhibitors through InSilico Ligand- and Structure-Based Approaches.

Non-nucleosidase reverse transcriptase inhibitors (NNRTIs) are highly promising agents for use in highly effective antiretroviral therapy. We implemented a rational approach for the identification of promising NNRTIs based on the validated ligand- and structure-based approaches. In view of our state-of-the-art techniques in drug design and discovery utilizing multiple modeling approaches, we report here, for the first time, quantitative pharmacophore modeling (HypoGen), docking, and in-house database screening approaches in the identification of potential NNRTIs. The validated pharmacophore model with three hydrophobic groups, one aromatic ring group, and a hydrogen-bond acceptor explains the interactions at the active site by the inhibitors. The model was implemented in pharmacophore-based virtual screening (in-house and commercially available databases) and molecular docking for prioritizing the potential compounds as NNRTI. The identified leads are in good corroboration with binding affinities and interactions as compared to standard ligands. The model can be utilized for designing and identifying the potential leads in the area of NNRTIs.

Understanding the role of ACE-2 receptor in pathogenesis of COVID-19 disease: a potential approach for therapeutic intervention.

Angiotensin-converting enzyme (ACE) and its homologue, ACE2, are commonly allied with hypertension, renin-angiotensin-aldosterone system pathway, and other cardiovascular system disorders. The recent pandemic of COVID-19 has attracted the attention of numerous researchers on ACE2 receptors, where the causative viral particle, SARS-CoV-2, is established to exploit these receptors for permitting their entry into the human cells. Therefore, studies on the molecular origin and pathophysiology of the cell response in correlation to the role of ACE2 receptors to these viruses are bringing novel theories. The varying level of manifestation and importance of ACE proteins, underlying irregularities and disorders, intake of specific medications, and persistence of assured genomic variants at the ACE genes are potential questions raising nowadays while observing the marked alteration in response to the SARS-CoV-2-infected patients. Therefore, the present review has focused on several raised opinions associated with the role of the ACE2 receptor and its impact on COVID-19 pathogenesis.