Higher Binding Potential Research Articles

Identification of Potential Inhibitors of TGFβR1 for the treatment of Cancer through Structure-based virtual screening and Molecular dynamics simulations.

Globally, cancer is one of the leading causes of death. Resistance to conventional medications, such as chemotherapy and radiation, continues to be a significantchallenge in the treatment of cancerdespite the availability of numerous medicines. Therefore, the highest priority is to hunt for new therapeutic agents. Transforming growth factor-beta is a pivotal regulatory cytokine that exerts significant influence over cellular processes, particularly emphasizing its role in facilitating and modulating cell proliferation. TGFβ1,identified asmost promising active site of the TGF-β signaling, is a potent drug target site that has garnered wide attention for developing new anticancer agents. The present investigation investigates the potential phytochemicals as TGFβR1 inhibitors. The SB431542 complexed TGFβR1 protein model was used to screen the natural product database to obtain a compound with high binding potential. NPC247629 has emerged as the best-scored compound among all the screened compounds, demonstrating the highest affinity towards the TGFβR1 regarding docking score -17.54 kcal/mol. TheMD simulation study indicated that all proposed hits are retained inside the receptor in dynamic states. The best-screened hits, NPC247629 and NPC60735, have excellent binding affinity and hold a massive potential for TGFβR1 inhibition, paving the way for promising future investigations in cancer treatment.

Mitochondrial toxicity of selected natural compounds: in vitro assessment and in silico molecular docking and dynamics simulation

Prangos uechtritzii Boiss & Hausskn stands out for its rich bioactive constituents including prantschimgin (PRA), imperatorin (IMP), suberosin (SUB), adicardin (ADI), and oxypeucedanin hydrate (OPH) in the Apiaceae family. Although these molecules contribute to several biological activities, their mitochondrial toxicity were not illuminated in depth with the appropriate in vitro and in silico models. Cell viability studies investigated the cytotoxic activities of molecules in HepG2 cells by replacing glucose with galactose due to Warburg effects. Mitochondrial toxicity (mitotoxicity) parameters such as cellular adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels were assessed with cytotoxic concentrations of selected molecules. Molecular docking and dynamics studies were also conducted against mitochondrial electron transport chain (ETC) complexes (I-V) with selected compounds. In vitro results showed that PRA, SUB, and IMP reduced cell viability more in galactose media compared to high glucose media in a dose-dependent manner. PRA, IMP, and SUB decreased ATP levels and MMP, especially in the galactose medium. The in silico study revealed that PRA, IMP, and SUB might bind to complexes I-V at different levels. The docking study demonstrated that PRA had the highest binding potential with the complexes, higher than the standard ligands in some cases. The molecular dynamics (MD) simulation study showed that PRA formed stable complexes with complexes II, III, and IV. In addition, PRA was anticipated to remain inside the binding site of complex II most stably during the 230 ns simulation period. Our study suggests that PRA, IMP, and SUB exhibit mitotoxicity.

Synthesis of Novel Cu(II), Co(II), Fe(II), and Ni(II) Hydrazone Metal Complexes as Potent Anticancer Agents: Spectroscopic, DFT, Molecular Docking, and MD Simulation Studies.

Metal complexes [FeL], [NiL]·H2O, [CuL], and [CoL]·H2O were formed by the ligand (L, 4-fluoro-N'-(2-hydroxybenzylidene)benzohydrazide) reacting with Fe(OAc)2, Ni(OAc)2·4H2O, Cu(OAc)2·H2O, and Co(OAc)2·4H2O. The produced compounds were characterized using a variety of methods, such as NMR, UV-vis, FT-IR, magnetic susceptibility, elemental analysis, and molar conductivity. The spectrum of the data indicates that the geometry of the complex molecular structures is octahedral with six coordination sites. The ligand and its different metal complexes were tested in a human lung cancer cell line and a normal embryonic kidney cell line. A cytotoxic assay revealed that L-Cu is the most potent chelate against cancer cell lines. A computational study was performed to rationalize this finding. The binding potential of relatively active compounds to a suitable target was analyzed. For this purpose, a target that is known to be inhibited by small compounds with a scaffold similar to that of the synthesized compounds, lysine-specific demethylase 1 (LSD1), was first determined. Molecular docking studies demonstrated that L-Cu has a high binding potential to LSD1 at a level comparable to that of a standard ligand. Molecular dynamics (MD) simulations revealed that L-Cu and L form stable complexes with the enzyme. Furthermore, the MD simulation study showed that L-Cu remained inside the binding pocket of the enzyme during the 200 ns simulation period. Density functional theory (DFT) studies demonstrated that the chemical stability of L was higher than that of its chelate form, L-Cu.

Medial prefrontal neuroplasticity during extended-release naltrexone treatment of opioid use disorder – a longitudinal structural magnetic resonance imaging study

Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of μ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and μ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX’s distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.

Brain inflammation co-localizes highly with tau in mild cognitive impairment due to early-onset Alzheimer's disease.

Brain inflammation, with an increased density of microglia and macrophages, is an important component of Alzheimer's disease (AD) and a potential therapeutic target. However, it is incompletely characterized, particularly in patients whose disease begins before the age of 65 years and, thus, have few co-pathologies. Inflammation has been usefully imaged with translocator protein (TSPO) positron emission tomography (PET), but most inflammation PET tracers cannot image subjects with a low-binder TSPO rs6971 genotype. In an important development, participants with any TSPO genotype can be imaged with a novel tracer, [11C]ER176, that has a high binding potential and a more favorable metabolite profile than other TSPO tracers currently available. We applied [11C]ER176 to detect brain inflammation in mild cognitive impairment (MCI) caused by early-onset AD. Furthermore, we sought to correlate the brain localization of inflammation, volume loss, elevated Aβ and tau. We studied brain inflammation in 25 patients with early-onset amnestic MCI (average age 59 ± 4.5 years, 10 women) and 23 healthy controls (average age 65 ± 6.0 years, 12 women), both groups with a similar proportion of all three TSPO-binding affinities. [11C]ER176 total distribution volume (VT), obtained with an arterial input function, was compared across patients and controls using voxel-wise and region-wise analyses. In addition to inflammation PET, most MCI patients had Aβ (n=23), and tau PET (n=21). For Aβ and tau tracers, standard uptake value ratios (SUVRs) were calculated using cerebellar grey matter as region of reference. Regional correlations among the three tracers were determined. Data were corrected for partial volume effect. Cognitive performance was studied with standard neuropsychological tools. In MCI caused by early-onset AD, there was inflammation in the default network, reaching statistical significance in precuneus and lateral temporal and parietal association cortex bilaterally, and in the right amygdala. Topographically, inflammation co-localized most strongly with tau (r= 0.63 ± 0.24). This correlation was higher than the co-localization of Aβ with tau (r= 0.55±0.25) and of inflammation with Aβ (0.43±0.22). Inflammation co-localized least with atrophy (-0.29±0.26). These regional correlations could be detected in participants with any of the three rs6971 TSPO polymorphisms. Inflammation in AD-related regions correlated with impaired cognitive scores. Our data highlight the importance of inflammation, a potential therapeutic target, in the AD process. Furthermore, they support the notion that, as shown in experimental tissue and animal models, the propagation of tau in humans is associated with brain inflammation.

Reverse vaccinology approach for identification of epitopes from E1 protein as peptide vaccine against HCV: A proof of concept

The development of effective vaccines against Hepatitis C Virus (HCV) remains a global health priority and challenge. In this study, we employed an integrative approach combining computational epitope prediction with experimental validation to identify immunogenic peptides targeting the E1 glycoprotein of HCV. In the present report, computational data from various epitope prediction algorithms such as IEDB and SYFPEITHI, followed by molecular dynamics (MD) simulations and immuno-informatics analysis is presented. Through computational screening, we identified potential epitope candidates, with QVRNSSGLY (P3) and QLFTFSPRH (P7) emerging as promising candidates. MD simulations revealed stable interactions between these epitopes and MHC molecule, further validated by free energy estimations using MMPBSA method. Immuno-informatics analysis supported these findings, showing high binding potential and immunogenicity scores for the selected peptides. Subsequent synthesis and characterization of epitope peptides confirmed their structural integrity and purity required for conducting immune activation assays. Experimental immunological assays carried out in this study involved epitope peptide induced activation of CD8 + and CD4 + T cells from healthy human subjects and HCV- recovered patients. Data from experimental validation revealed significant cytokine release upon exposure to epitope peptides, particularly TNF-a, IL-6, and GM-CSF, indicative of robust immune responses. Notably, peptides P3 and P7 exhibited the most pronounced cytokine induction profiles, underscoring their potential as vaccine candidates. Further investigations addressing the mechanism of action of these epitope peptides under preclinical and clinical settings may help in developing effective vaccine against HCV.

Isolation and characterization of thymoquinone from Nigella sativa essential oil: antioxidant and antibacterial activities, molecular modeling studies, and cytotoxic effects on lung cancer A549 cells

Thymoquinone (TQ), a bioactive compound found in Nigella sativa seeds, has gained considerable attention due to its potential therapeutic properties. This study aimed to isolate and characterize TQ from Nigella sativa essential oil and evaluate its antioxidant capacity, antibacterial activity, and cytotoxic effects on lung cancer A549 cells. Moreover, The binding potential of TQ to Keap1 (Kelch-like ECH associated protein 1) was investigated through molecular docking. The stability of the resulting complex was evaluated through molecular dynamics (MD) simulation. The CUPRAC assay revealed significant antioxidant capacity of TQ, as indicated by its high molar absorptivity coefficient. TQ also demonstrated notable free radical scavenging activity, with efficacy increasing with concentration. In terms of antiquorum sensing activity, TQ displayed effectiveness against all tested virulence factors in P. aeruginosa PAO1 and Chromobacterium violaceum in different range. Additionally, TQ induced cytotoxicity in non-small lung cancer cells, inhibiting cell viability. In conclusion, this study successfully isolated and characterized TQ from Nigella sativa seeds and demonstrated its remarkable antioxidant capacity, antibacterial activity, and cytotoxic effects on lung cancer cells. These findings suggest the potential of TQ for various applications in the food and pharmaceutical industries. The wet-lab study demonstrated that TQ had an antioxidant effect. The TQ was found to have high binding potential to Keap1 as it formed four conventional hydrogen bonds with the protein. The resulting Keap1-TQ complex was also found to be stable. Further research is warranted to explore the therapeutic potential of TQ and develop novel treatments based on its properties.

Development of simultaneous determination of dopamine 2, histamine 1, and muscarinic acetylcholine receptor occupancies by antipsychotics using liquid chromatography with tandem mass spectrometry

Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 μg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 μg/kg raclopride, 10 μg/kg doxepin, and 30 μg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70–95%, 19–43%, and 12–45%, respectively, at an olanzapine dose range of 3–10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.

Lipooligosaccharide Ligands from Respiratory Bacterial Pathogens Enhance Cellular Uptake of Nanoparticles

Several bacterial pathogens contain membrane ligands that facilitate their binding and internalization into human tissues. In this study, lipooligosaccharides (LOS) from the respiratory pathogen non-typeable Haemophilus influenzae (NTHi) were isolated from the bacterial surface and evaluated as a nanoparticle coating material to facilitate uptake into respiratory epithelium. NTHi clinical isolates were screened to select a strain with high binding potential due to their elevated phosphorylcholine content. The association of particles with human bronchial epithelial cells was investigated as a function of particle surface chemistry and incubation time, and the uptake mechanism evaluated via chemical inhibitor and receptor activation studies. A more than two-fold enhancement in particle uptake was achieved by coating the particles with LOS compared to uncoated or gelatin-coated particles, which was further increased by activating the platelet activating factor receptor (PAFR). These findings demonstrate that bacterial-derived LOS ligands can enhance the targeting and binding of nanoparticles to lung epithelial cells.

TOWARDS UNDERSTANDING NATURAL ALPHA-GLUCOSIDASE INHIBITORS: A COMPUTATIONAL STUDY

Objective: Diabetes mellitus is a metabolic disorder affecting hundreds of millions of people around the world. It is characterized by hyperglycemia caused by impaired glucose homeostasis that results from insufficient insulin production or insulin resistance. There are clinically available α-glucosidase inhibitor drugs that are used to decrease postprandial blood glucose level. However, these drugs have side effects that necessitated the discovery of new α-glucosidase inhibitors with less side effects and high potency. The interest in the use of natural products to deal with diabetes has been increasing. Therefore, the potential of natural α-glucosidase inhibitors to inhibit the enzyme was investigated through computational methods. Material and Method: The binding potential of selected natural α-glucosidase inhibitors was investigated through molecular docking. Thereafter, the stability of the complexes with the highest binding potential were assessed through molecular dynamics (MD) simulation. Result and Discussion: The molecular docking demonstrated that compound 2 had better binding potential than the standard drug, acarbose. Compound 7 had comparable binding potential to the standard drug. Furthermore, all the tested compounds exhibited a reasonable binding potential towards the enzyme but were weaker than the standard drug. The MD simulation demonstrated that compounds 2 and 7 gave complexes with similar stability to the standard drug. The overall computational results revealed that the natural inhibitors investigated had the ability to bind to the enzyme and formed stable complexes. Therefore, these compounds could be potential α-glucosidase inhibitors for clinical use. For this reason, further in vitro investigations on compounds with the highest binding potential is recommended.

Biological reduction of aflatoxin M1 in dairy products using probiotic strains: a systematic review and meta-analysis

Abstract Aflatoxins are naturally occurring toxic substances produced mainly by species of the genus Aspergillus that can contaminate almost all foodstuffs. Apart from the harmful effects they have on human and animal health, they can be secreted unchanged in animal milk and cause contamination of milk and its products. Aflatoxin M1 (AFM1) is the major and most toxic type of aflatoxin after aflatoxin B1 (AFB1). The use of probiotic strains to reduce the amount of aflatoxin in milk and by-products has been observed in many studies. In this systematic review and meta-analysis, articles in PubMed, Scopus, Google Scholar and ISI Web of Science were searched to find eligible studies that reported reduction of AFM1 using probiotics in dairy products. The results were pooled using a random-effects model. In most studies, the efficiency of probiotics in milk has been tested by Lactobacillus strains. The results indicated that probiotic microorganisms could significantly reduce AFM1 by 55.76% (confidence interval (CI): 54.35%, 57.16%; I2 = 100%). Besides, the rank order of AFM1 reduction in dairy products based on probiotic strain subgroup was: Lactobacillus 51.99% (CI: 50.14%, 53.85%, I2 = 100%), Saccharomyces 67.36% (CI: 65.05%, 69.67%, I2 = 100%), Bifidobacterium 54.80% (CI: 54.18%, 55.43%, I2 = 99.9%), and 61.90% (CI: 53.80%, 70.00%, I2 = 100%) by a mix of strains. Considering the high binding potential of AFM1 to probiotic strains, these microorganisms can be recommended as a safe system to reduce AFM1 in dairy products.

Moderate DNA and high SARS-CoV-2 spike protein affinity of oxidovanadium(IV) complexes of 2-furoic acid hydrazones: In silico and in vitro approach

The interaction of five neutral heteroleptic octahedral paramagnetic mononuclear oxidovanadium(IV) complexes of general composition [VIVO(bpy)L], where L is a dianionic tridentate ONO-donor hydrazone ligand derived from 2-furoic acid hydrazide and salicylaldehyde and its 5-substituted derivatives with spike protein SARS-CoV-2 was investigated in silico and in vitro. Molecular docking indicates that the complexes have high affinity for SARS-CoV-2 spike protein binding, and that the complex with a nitro substituent on the salicylaldehyde component of the hydrazone ligand has the highest binding potential. The interaction of this complex was examined by spectrofluorimetry utilizing spectrofluorimetric titration, thermodynamic measurements and FRET analysis. The results suggest van der Walls forces and hydrogen bonding as the dominant modes of interaction of the complex with the SARS-CoV-2 spike protein, which is in agreement with theoretical predictions. Molecular docking was further employed to investigate the interaction of vanadium complexes with SARS-CoV-2 omicron variant (BA.1) RBD with human ACE2 protein. The interaction of the complex with CT DNA was investigated using electron spectroscopy and thermodynamic considerations. The complexes showed a moderate affinity for DNA as groove binders. The groove binding was confirmed by molecular docking with B-DNA. Also, druglikness properties of complexes were assessed by SwissADME. The strong antioxidant activity of the complexes, comparable to ascorbic acid, was evaluated by the DPPH method. This is the first experimental research that supports the thesis of molecular docking that vanadium compounds could be druggable against SARS-CoV-2 virus proteins.

Computational screening and MM/GBSA-based MD simulation studies reveal the high binding potential of FDA-approved drugs against Cutibacterium acnes sialidase

Cutibacterium acnes is an opportunistic pathogen linked with acne vulgaris, affecting 80–90% of teenagers globally. On the leukocyte (WBCs) cell surface, the cell wall anchored sialidase in C. acnes virulence factor, catalysing the sialoconjugates into sialic acids and nutrients for C. acnes resulting in human skin inflammation. The clinical use of antibiotics for acne treatments has severe adverse effects, including microbial dysbiosis and resistance. Therefore, identifying inhibitors for primary virulence factors (Sialidase) was done using molecular docking of 1030 FDA-approved drugs. Initially, based on binding energies (ΔG), Naloxone (ZINC000000389747), Fenoldopam (ZINC000022116608), Labetalol (ZINC000000403010) and Thalitone (ZINC000000057255) were identified that showed high binding energies as −10.2, −10.1, −9.9 and −9.8 kcal/mol, respectively. In 2D analysis, these drugs also showed considerable structural conformer of hydrogen and hydrophobic interactions. Further, a 100 ns MD simulation study found the lowest deviation and fluctuations with various intermolecular interactions to stabilise the complexes. Out of 4, the Naloxone molecule showed robust, steady, and stable RMSD 0.23 ± 0.18 nm. Further, MMGBSA analysis supports MD results and found strong binding energy (ΔG) −29.71 ± 4.97 kcal/mol. In Comparative studies with Neu5Ac2en (native substrate) revealed naloxone has a higher affinity for sialidase. The PCA analysis showed that Naloxone and Thalitone were actively located on the active site, and other compounds were flickered. Our extensive computational and statistical report demonstrates that these FDA drugs can be validated as potential sialidase inhibitors. Communicated by Ramaswamy H. Sarma

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

AbstractThe importance of R&D of new antivirals has been highly evident with the emergence of the pandemic caused by SARS‐CoV‐2. Pyrimidines are heterocyclic compounds with a broad biological spectrum. In this review we emphasize the antiviral application of pyrimidines. Scientific articles, drug and patent registrations were searched using terms involving antiviral pyrimidines. Between 2012 and 2022, more than 100 articles, which show the broad antiviral spectrum of these compounds, were added in this review. The publications of the last five years were prioritized. Anti‐HIV applications were found, their use more evident within the framework of antivirals; among others found were anti‐influenza, anti‐arboviral, and anti‐hepatitis viruses. The results found in the drug and patent databases corroborate the scenario observed in the analysis of scientific articles and demonstrate the importance of researching pyrimidine compounds in periods of great impact on global health. Additionally, through virtual screening of 119 pyrimidines from an in‐house library, we found seventeen pyrimidines with high binding potential with the Mpro and RdRp proteins of SARS‐CoV‐2. Almost all seventeen compounds showed good pharmacokinetic and toxicological profile, mainly compounds 150 and 151 being considered promising for biological evaluation against SARS‐CoV‐2.

Role reversal of silica nanoparticles with bovine trypsin from enzyme inhibitor to enzyme activator on surface modification

Silica nanoparticles (SiNPs) are one of the most extensively used nanoparticles, which are employed in diverse fields such as bioimaging, drug delivery, biosensing, etc. In this study, SiNPs were synthesized using condensation method, with further surface functionalization using 3-aminopropyltetraethoxysilane (APTES) to facilitate the formation of bioactive conjugates. These nanoparticles were characterized using SEM, HR-XRD, TEM, DLS, FTIR, and TGA. Further, comparative studies for determining the effect of SiNPs and SiNPs@APTES on the structure and activity of bovine trypsin were performed using different physicochemical techniques, accompanied by enzymatic activity assay. UV-Visible, FTIR, and fluorescence studies indicated a possible change in the conformation of trypsin due to both types of nanoparticles. The quantitative analysis using UV-Visible data showed that the SiNPs (KBH = 5.50 ×104 M-1) have higher binding potential, as compared to that of SiNPs@APTES (KBH = 2.96 ×104 M-1). CD results showed that SiNPs destabilize the structure of trypsin, while SiNPs@APTES provide an overall stabilizing effect. Enzymatic activity studies revealed that SiNPs@APTES work as an activator, while SiNPs work as an inhibitor for trypsin activity, suggesting the role reversal of SiNPs on surface modification. Our studies strongly suggest that SiNPs and SiNPs@APTES can be employed for regulating trypsin activity for biomedical applications.

Himalayan Citrus jambhiri juice reduced renal crystallization in nephrolithiasis by possible inhibition of glycolate oxidase and matrix metalloproteinases.

Citrus fruits are a very rich source of electrolytes and citric acid. They have been used traditionally for treating urinary ailments and renal stones. Citrus jambhiri is indigenously used as a diuretic. Present study aimed at establishing the antiurolithiatic potential of the juice of Citrus jambhiri fruits along with the elucidation of the mechanism involved in the urolithiasis disease defying activity. The antiurolithiatic activity was established by means of nucleation, growth and aggregation assay in the in vitro settings and by means of ethylene glycol mediated calcium oxalate urolithiasis in the male Wistar rats. Docking studies were performed in an attempt to determine the mechanism of the antiurolithiatic action. Present study revealed the role of C. jambhiri fruit juice in reducing nucleation, growth and aggregation of calcium oxalate crystals by possible reduction in the urinary supersaturation relative to calcium oxalate and raising the zeta potential of the calcium oxalate crystals. C. jambhiri fruit juice treatment in experimental rats produced significant amelioration of hypercalciuria, hyperoxaluria, hyperphosphaturia, hyperproteinuria, hyperuricosuria, hypocitraturia and hypomagnesiuria and ion activity product of calcium oxalate. It exhibited nephroprotection against calcium oxalate crystals induced renal tubular dilation and renal tissue deterioration. Docking studies further revealed high binding potential of the phytoconstituents of C. jambhiri viz. narirutin, neohesperidin, hesperidin, rutin and citric acid with glycolate oxidase and matrix metalloproteinase-9. C. jambhiri fruit juice possesses excellent antiurolithiatic activity. The study reveals antiurolithiatic mechanism that involves restoration of equilibrium between the promoters and inhibitors of stone formation; and inhibition of matrix metalloproteinases and glycolate oxidase.

Local QSAR modeling of cytotoxic activity of newly designed androstane 3-oximes towards malignant melanoma cells

As one of the deadliest forms of skin cancers, malignant melanoma is the most common cause of death from this type of cancer. Malignant melanoma has a steadily increasing incidence and the medical treatment options are still quite limited. One of the possible options for malignant melanoma treatment is medication therapy. The present study is focused on the development of new compounds that can be possibly used for malignant melanoma treatment. A newly synthesized series of alkylaminoethyl derivatives of androstane 3-oximes expressed significant cytotoxic activity towards malignant melanoma cells. This was an excellent basis for the development of quantitative structure-activity relationship (QSAR) models for the prediction of cytotoxic activity of not yet synthesized compounds. Also, on the basis of the cytotoxic activity data the molecular docking and molecular dynamics analysis were carried out. This local QSAR modeling, which is based on a limited set of structurally similar compounds, resulted in one univariate linear regression model, four multiple linear regression models and five support vector machines models. All of the models were confirmed to be statistically reliable with quite good prediction ability. The results of comparative molecular docking and molecular dynamics analysis indicated a high binding potential of novel compounds in regards to cisplatin as well-known chemotherapy drug. The established QSAR models and the results of molecular docking and molecular dynamics can be considered to be the guidelines for the design of new compounds worth synthesizing as potential lead compounds for malignant melanoma treatment.

Antioxidant Phenolics of Justicia adhatoda L. and Cordia dichotoma Frost. Promote Thrombolytic Activity through Binding to a Serine Protease, Tissue Plasminogen Activator Protein

Abstract Background: The tissue plasminogen activator (tPA) protein dissolutes fibrin clots and prevents the disease like thrombosis. The current study aimed to study the tPA-promoting activity of bioactive molecules of Justicia adhatoda L (JA) and Cordia dichotoma Frost (CD). Methods: The phytochemical characterization of methanolic and aqueous extracts of JA and CD stems was performed through qualitative analysis, Fourier-transform infrared spectroscopy (FTIR), and biochemical tests (total phenolic and total flavonoid content [TPC and TFC]). The bioactivity of the extracts was studied through total antioxidant capacity (TAC) and ferric-reducing antioxidant potential (FRAP) assays. Finally, forty phytocompounds from JA and CD were identified from the literature, and in silico molecular docking study was performed to target tPA protein (PDB id 1A5H, Chain A, X-ray diffraction, resolution 2.90 Å). Results: Various phytochemical classes were identified from extracts, through qualitative and FTIR analysis. TPC and TFC were estimated from the JA and CD extracts within the range of 9.34–28.67 mg gallic acid equivalent/100 g of extract weight (EW) and 2.48–16.17 mg quercetin equivalent/100 g of EW, respectively. The aqueous extract of CD showed the highest TAC of 14.90 ascorbic acid equivalent (AAE)/100 g of EW, and the methanolic extract of JA had the highest FRAP activity of 27.77 mg AAE/100 g EW. The molecular docking study showed that apigenin 6,8-di-glucopyranoside had the highest binding potential toward the tPA (−9.380 kcal/mol). Conclusion: It can be concluded that antioxidant phytochemicals of JA and CD could promote the tPA activity, thereby promoting thrombolytic activity.

Prediction of the Endocrine disruption profile of fluorinated biphenyls and analogues: An in silico study

Fluorinated biphenyls and their analogues (FBAs) are considered new persistent organic pollutants, but their endocrine-disrupting effects are still unknown. To fill this gap, the binding probability of 44 FBAs to different nuclear hormone receptors (NHRs) was predicted using Endocrine Disruptome. And molecular similarity and network toxicology analysis were used to strengthen the docking screening. The docking results showed that FBAs could have high binding potential for various NHRs, such as estrogen receptors β antagonism (ERβ an), liver X receptors α (LXRα), estrogen receptors α (ERα), and liver X receptors β (LXRβ). The similarity analysis found that the degree of overlap of the NHR repertoire was related to the Tanimoto coefficient of FBAs. Network toxicology verified a part of docking screening results and identified endocrine-disrupting pathways worthy of attention. This study found out potential endocrine-disrupting FBAs and their vulnerable, and developed a workflow that would leverage in silico approaches including molecular docking, similarity, and network toxicology for risk prioritization of potential endocrine-disrupting compounds.

Computational Repurposing of Mitoxantrone-Related Structures against Monkeypox Virus: A Molecular Docking and 3D Pharmacophore Study.

Monkeypox is caused by a DNA virus known as the monkeypox virus (MPXV) belonging to the Orthopoxvirus genus of the Poxviridae family. Monkeypox is a zoonotic disease where the primary significant hosts are rodents and non-human primates. There is an increasing global incidence with a 2022 outbreak that has spread to Europe in the middle of the COVID-19 pandemic. The new outbreak has novel, previously undiscovered mutations and variants. Currently, the US Food and Drug Administration (FDA) approved poxvirus treatment involving the use of tecovirimat. However, there has otherwise been limited research interest in monkeypox. Mitoxantrone (MXN), an anthracycline derivative, an FDA-approved therapeutic for treating cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against the vaccinia virus and monkeypox virus. In this study, virtual screening, molecular docking analysis, and pharmacophore ligand-based modelling were employed on anthracene structures (1-13) closely related to MXN to explore the potential repurposing of multiple compounds from the PubChem library. Four chemical structures (2), (7), (10) and (12) show a predicted high binding potential to suppress viral replication.