Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Exploring Type II Diabetes Inhibitors from Genus Daphne Plant-species: An Integrated Computational Study.

BACKGROUND: Plant species of the genus Daphne clasps a historical background with a potential source of bioactive phytochemicals such as flavonoids and daphnodorins. These compounds manifest a significant chemotaxonomic value in drug discovery. Their flair comprehensive pharmacological, phytochemical, biological, catalytic, and clinical utilities make them exclusively unique. This study was conducted to investigate the optimization and structure-based virtual screening of these peculiar analogs. The majority of the active constituents of medicines are obtained from natural products. Previously, before the invention of virtual screening methods or techniques, almost 80% of drugs were obtained from natural resources. Comparing reported data to drug discovery from 1981 to 2007 signifies that half of the FDA-approved drugs are obtained from natural resources. It has been reported that structures of natural products that have particularities of structural diversity, biochemical specification, and molecular properties make them suitable products for drug discovery. These products basically have unique chiral centers which increase their structural complexity than the synthesized drugs. METHOD: This work aimed to probe the use of daphnodorins analogs for the first time as antidiabetic inhibitors based on significant features and to determine the potential of daphnodorin analogs as antidiabetic inhibitors through computational analysis and structure-based virtual screening. A dataset of 38 compounds was selected from different databases, including PubChem and ZINC, for computational analysis, and optimized compounds were docked against various co-crystallized structures of inhibitors, antagonists, and receptors which were downloaded from PDB by using AutoDock Vina (by employing Broyden-Fletcher-Goldfarb-Shanno method), Discovery studio visualizer 2020, PYMOL (Schrodinger). Docking results were further validated by Molecular dynamic simulation and MM-GBSA calculation. Quantitative structure-activity relationship (QSAR) was reported by using Gaussian 09W by intimating Density Functional Theory (DFT). Using this combination of multi-approach computational strategy, 14 compounds were selected as potential exclusive lead compounds, which were analyzed through ADMET studies to pin down their druglike properties and toxicity. RESULT: At significant phases of drug design approaches regular use of molecular docking has helped to promote the separation of important representatives from 38 pharmaceutically active compounds by setting a threshold docking score of -9.0 kcal/mol which was used for their exposition. Subsequently, by employing a threshold it was recognized that 14 compounds proclaimed this threshold for antidiabetic activity. Further, molecular dynamic simulation, MM-GBSA, ADMET, and DFT results screened out daphnegiralin B4 (36) as a potential lead compound for developing antidiabetic agents. CONCLUSION: Our analysis took us to the conclusion that daphnegiralin B4 (36) among all ligands comes out to be a lead compound having drug-like properties among 38 ligands being non-carcinogenic and non-cytotoxic which would benefit the medical community by providing significant drugs against diabetes. Pragmatic laboratory investigations identified a new precursor to open new doors for new drug discovery.

Accelerating antibiotic access and stewardship: a new model to safeguard public health.

This Personal View discusses the challenges faced, especially by low-income and middle-income countries (LMICs), in responding to the growing burden of bacterial antimicrobial resistance. Many patients in LMICs lack access to effective and affordable treatments needed to successfully treat patients. Meanwhile, traditional antimicrobial stewardship models face implementation challenges due to financial, health system, and human resource constraints. These constraints call for a paradigm shift from traditional high-income country-style antimicrobial stewardship, which is often resource intensive and aimed at cost containment, to a broader concept of sustainable access. We suggest a model of context-adapted stewardship that continues to emphasise providing the right antibiotic, at the right time, for the right duration, and at an affordable price. Taking lessons from other disease areas, including tuberculosis, we identify interventions such as task shifting to various health-care workers and the implementation of a hub-and-spoke model to support appropriate use of antibiotics, to enable optimal access and maximisation of scarce resources.

Estimation of dietary intake of sodium, potassium, phosphorus and protein in healthy Indian population and patients with chronic kidney disease.

Introduction: Poor nutritious diet is a major risk element for non-communicable diseases (NCD), which are of considerable public health concern. Given the diverse dietary patterns in India, precise determination of nutrient consumption is crucial for disease management. The present study assessed the dietary intake of sodium, potassium, protein, and phosphorus among North Indians. Methods: This cross-sectional study included healthy adults and adults with stage 2 to 4 chronic kidney disease (CKD). We analysed sodium, protein, potassium and phosphorus intakes using one-time 24-h urinary excretion. Dietary intake was also analysed in subgroups based on sex, body mass index, blood pressure and abdominal obesity. We evaluated the performance of various equations available to estimate sodium intake using a spot urine sample with respect to the sodium excretion measured in a 24-h urine sample. Descriptive statistics was used along with t-test for statistical significance. Results: A total of 404 subjects (182 adult healthy subjects and 222 adults with CKD) with a mean age of 47.01 ± 11.46 years were studied. Mean dietary intakes of sodium, salt, potassium, protein and phosphorus were 2.94 ± 1.68 g/day, 7.42 ± 4.24 g/day, 1.43 ± 0.59 g/day, 47.67 ± 14.73 g/day and 0.86 ± 0.39 g/day, respectively. There were no differences in nutrient consumption between adults who were healthy and those with CKD. Consumption of sodium, salt, protein, potassium, and phosphorus among healthy population vs. those with CKD were 2.81 ± 1.60 vs. 3.05 ± 1.73 g/day (p = 0.152), 7.08 ± 4.04 vs. 7.70 ± 4.37 g/day (p = 0.143), 47.16 ± 14.59 vs. 48.08 ± 14.86 g/day (p = 0.532), 1.38 ± 0.59 vs. 1.48 ± 0.58 g/day (p = 0.087) and 0.86 ± 0.41 vs. 0.87 ± 0.37 g/day (p = 0.738), respectively. Men had higher consumption of these nutrients than women. Compared to non-hypertensives, hypertensive subjects had higher consumption of salt (8.23 ± 4.89 vs. 6.84 ± 3.59 g/day, p = 0.002) and potassium (1.51 ± 0.63 vs. 1.38 ± 0.55 g/day, p = 0.024), however, no difference were found in protein and phosphorus intakes. In terms of performance of equations used to estimate 24-h sodium intake from spot urinary sodium concentration against the measured 24-h urinary sodium excretion, INTERSALT 2 equation exhibited the least bias [1.08 (95% CI, -5.50 to 7.66)]. Conclusion: The study shows higher-than-recommended salt and lower-than-recommended potassium intake in the north Indian population compared to those recommended by guidelines. The dietary protein intake is below the recommended dietary allowance. These findings help the development of targeted policies for dietary modification to reduce the risk of the development and progression of CKD.

A virtual insight into mushroom secondary metabolites: 3D-QSAR, docking, pharmacophore-based analysis and molecular modeling to analyze their anti-breast cancer potential.

Breast cancer is a major issue of investigation in drug discovery due to its rising frequency and global dominance. Plants are significant natural sources for the development of novel medications and therapies. Medicinal mushrooms have many biological response modifiers and are used for the treatment of many physical illnesses. In this research, a database of 89 macro-molecules with anti-breast cancer activity, which were previously isolated from the mushrooms in literature, has been selected for the three-dimensional quantitative structure-activity relationships (3D-QSAR) studies. The 3D-QSAR model was necessarily used in Pharmacopoeia virtual evaluation of the database to develop novel MCF-7 inhibitors. With the known potential targets of breast cancer, the docking studies were achieved. Using molecular dynamics simulations, the targets' stability with the best-chosen natural product molecule was found. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity of three compounds, resulting after the docking study, were predicted. The compound C1 (Pseudonocardian A) showed the features of effective compounds because it has bioavailability from different coral species and is toxicity-free for the prevention of many dermatological illnesses. C1 is chemically active and possesses charge transfer inside the monomer, as seen by the band gaps of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) electrons. The reactivity descriptors ionization potential, electron affinity, chemical potential (µ), hardness (η), softness (S), electronegativity (χ), and electrophilicity index (ω) have been estimated using the energies of frontier molecular orbitals (HOMO-LUMO). Additionally, molecular electrostatic potential maps were created to show that the C1 is reactive.Communicated by Ramaswamy H. Sarma.

The selected compounds from the mushroom were evaluated as potential breast cancer MCF-7 cell line inhibitor.Ligand-based 3D-QSAR study to analyze the structurally diverse compounds with experimentally reported IC₅₀.Pharmacophore-based virtual screening of compounds.Molecular docking analysis pointed out the vital interaction of the hit with the protein's amino acids.Absorption, distribution, metabolism, and excretion (ADME) and toxicity properties of the lead compounds were examined.

A discovery of potent kaempferol derivatives as multi-target medicines against diabetes as well as bacterial infections: an in silico approach.

Flavonoids demonstrate beneficial effects on human health because flavonoids contain important biological properties. Kaempferol is a flavonol, type of flavonoid found in eatable plants and in plants usually employed in ancient drugs (Moringa oleifera, Tilia spp., fern genus spp. and gingko etc.). Some medicinal studies have shown that the use of foods full of kaempferol decreases the risk of many (cancer, vascular) diseases. All the data of 50 kaempferol derivatives were collected from PubChem database. Through Schrödinger software, 3D-QSAR study was performed for 50 compounds by using method of field base. Conformer of kaempferol derivatives was docked against anti-diabetic, anti-microbial co-crystal structures and protein. To monitor the best anti-diabetic and antibacterial agent, particular kaempferol derivatives were downloaded from PubChem database. Virtual screening by molecular docking provided four lead compounds with four different proteins. These hit compounds were found to be potent inhibitor for diabetic enzymes alpha-amylase and DPP IV and had the potential to suppress DNA gyrase and dihydrofolate reductase synthesis. Molecular dynamic simulation of docked complexes evaluates the value of root mean square fluctuation by iMOD server. Kaempferol 3-O-alpha-L-(2, 3-di-Z-p-coumaroyl) rhamnoside (42) compound used as anti-diabetic and kaempferol 3-O-gentiobioside (3) as antibacterial with good results can be used for drug discovery.Communicated by Ramaswamy H. Sarma.

Design, synthesis, in-vitro biological profiling and molecular docking of some novel oxazolones and imidazolones exhibiting good inhibitory potential against acetylcholine esterase.

Heterocyclic compounds with oxazole and imidazole rings in their structure have disclosed momentous biological aptitudes. Taking into account their superlative attributes, the present study was designed to introduce a new synthetic scheme to make new derivatives with tremendous futuristic pharmacological potentialities. Series of Oxazolones were synthesized by using substituted benzaldehyde with benzyl halides to produce respective benzaldehyde derivatives 1 (a-d) which further reacted with hippuric acid to yield oxazolones 2 (a-e). Newly synthesized oxazolones then reacted with 4-chloroaniline to yield corresponding imidazolones 3 (a-e). All the compounds were characterized by using FTIR and NMR spectroscopic techniques. Docking studies of Compounds were conducted using AutoDock Vina and analyzed with PYMOL. All synthesized oxazolone and imidazolone derivatives exhibited antioxidant potential, demonstrated by their IC50 values compared to ascorbic acid standard. Oxazolone derivatives (2a-2e) exhibited good acetyl cholinesterase inhibitory potential whereas Imidazolone series did not show significant inhibition as shown by their IC50 values compared to donepezil as a standard. Docking studies of all compounds against acetylcholinesterase demonstrated favorable binding affinity, indicating their potential for further in-vivo studies. It is notable that novel compounds of both oxazolones and Imidazolone series exhibited antioxidant potential with maximum percentage inhibition of 75.9 (IC50 12.9 ± 0.0573 µM/mL) by compound 2d while compound 2a showed AChE inhibitory potential with maximum %age inhibition of 75.49 (IC50 7.8 ± 0.0218 µM/mL).Communicated by Ramaswamy H. Sarma.

An In Silico In Vitro and In Vivo Study on the Influence of an Eggplant Fruit (Solanum anguivi Lam) Diet on Metabolic Dysfunction in the Sucrose-Induced Diabetic-like Fruit Fly (Drosophila melanogaster).

Introduction: Africa faces immense food and health insecurity challenges, a problem partly attributed to food loss and waste during postharvest handling and distribution. In the context of research to meet the sustainable development goals, this project specifically addressed the postharvest loss of the ripe indigenous eggplant (Solanum anguivi lam) fruit called "Igba Yinrin" by Yoruba in South-West Nigeria, which is usually discarded in farms. The study was carried out on ripe and unripe fruits to better understand their value by comparing their effects in diabetes treatment. Methods: The study sought to assess the effects of a diet including ripe or unripe mature eggplant fruits in the sucrose-induced diabetic-like fruit fly. Bioactive compounds were identified and quantified with HPLC-UV, while the antioxidant vitamin (A, C, E), carotenoid, and mineral (Na, K, Ca, Mg, Fe, P, and Zn) content was analyzed in the fruits. Extracts were used to investigate their in vitro anti-inflammatory properties on cyclooxygenases (COX 1 and 2), 5-lipoxygenase (5-LOX), and anti-diabetes enzymes [α-amylase and α-glucosidase], while extract-supplemented diets (0.25-1% concentration) were fed to the fruit flies for 14 days. Results: Interestingly, the results showed that the ripe fruits had a significantly (p < 0.05) higher total phenol and flavonoid content, as well as a higher content of vitamins, carotenoids, and minerals, than the unripe fruits. The in vivo activities of antioxidant enzymes [superoxide dismutase (SOD), catalase (CAT), and glutathione transferase (GST)] and the total thiol level increased, while the blood glucose, reactive oxygen species (ROS), and malondialdehyde (MDA) levels decreased in Drosophila melanogaster (fruit fly). An in silico docking analysis showed strong binding affinity of the above-mentioned enzymes under investigation with the ligands hesperidin, naringin, and myricetin, which are bioactive compounds contained in the examined extracts. Conclusions: There was no significant difference in the biological effects of the ripe and unripe fruit extracts on inflammatory and anti-diabetes enzyme activities, which means that the ripe fruit, usually discarded, could serve as a sustainable alternative source of food nutrients.

Possible case of bortezomib-induced ileus paralytic.

This report describes a case of a patient with active multiple myeloma who was started on bortezomib, cyclophosphamide and dexamethasone and subsequently presented to the emergency department with acute intestinal obstruction one week later. The patient underwent exploratory laparotomy, but no mechanical cause of the obstruction was found. The patient later developed sepsis and eventually died. The possible cause of the intestinal obstruction was attributed to bortezomib, and the paper discusses the potential mechanism of this side effect and its management based on available literature.

Combined Experimental and Theoretical Insights: Spectroscopic and Molecular Investigation of Polyphenols from Fagonia indica via DFT, UV-vis, and FT-IR Approaches.

This review deals with computational study of polyphenolic compounds of medicinal importance and interest for drug development. Herein, four polyphenolic compounds comprising catechol (1), caffeic acid (II), gallic acid (III), and pyrogallol (IV) have been isolated from a medicinal specie, Fagonia indica, by applying silica gel column chromatography. These compounds were identified by using gas chromatography-mass spectrometry (GC-MS) analysis and confirmed by geometric computational analysis. According to computational results, caffeic acid has shown the highest biological activation due to higher chemical softness, electronegativity (χ (eV) = -648.644), and electrostatic potential value (-8.424 × 10-2 to +8.424 × 10-2), while smaller values of chemical potential (-0.269), ELUMO (-0.080), and energy gap (ΔE = 0.149). The Mulliken atomic charges were calculated by using DFT/B3LYP with basis set 6-311G for the determination of active sites. The oxygen atom of catechol showed highest nucleophilic characteristic with a more negative charge (08 = -0.695), and pyrogallol indicated a strong electrophilic center at C14 = 0.415 with a higher positive charge. Moreover, UV-visible absorption spectra and a detailed study of vibrational frequencies for all phenolic compounds by employing the DFT approach with 3-21G, 6-31G, and 6-311G basis sets at the ground-state level showed the great agreement with experimental results. ANOVA has been applied to validate the theoretical data. Results suggest that compounds I-IV are suitable in diverse fields.

Exploring Citrus sinensis Phytochemicals as Potential Inhibitors for Breast Cancer Genes BRCA1 and BRCA2 Using Pharmacophore Modeling, Molecular Docking, MD Simulations, and DFT Analysis.

BACKGROUND: Structure-activity relationship (SAR) is considered to be an effective in silico approach when discovering potential antagonists for breast cancer due to gene mutation. Major challenges are faced by conventional SAR in predicting novel antagonists due to the discovery of diverse antagonistic compounds. Methodologyand Results: In predicting breast cancer antagonists, a multistep screening of phytochemicals isolated from the seeds of the Citrus sinensis plant was applied using feasible complementary methodologies. A three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed through the Flare project, in which conformational analysis, pharmacophore generation, and compound alignment were done. Ten hit compounds were obtained through the development of the 3D-QSAR model. For exploring the mechanism of action of active compounds against cocrystal inhibitors, molecular docking analysis was done through Molegro software (MVD) to identify lead compounds. Three new proteins, namely, 1T15, 3EU7, and 1T29, displayed the best Moldock scores. The quality of the docking study was assessed by a molecular dynamics simulation. Based on binding affinities to the receptor in the docking studies, three lead compounds (stigmasterol P8, epoxybergamottin P28, and nobiletin P29) were obtained, and they passed through absorption, distribution, metabolism, and excretion (ADME) studies via the SwissADME online service, which proved that P28 and P29 were the most active allosteric inhibitors with the lowest toxicity level against breast cancer. Then, density functional theory (DFT) studies were performed to measure the active compound's reactivity, hardness, and softness with the help of Gaussian 09 software. CONCLUSIONS: This multistep screening of phytochemicals revealed high-reliability antagonists of breast cancer by 3D-QSAR using flare, docking analysis, and DFT studies. The present study helps in providing a proper guideline for the development of novel inhibitors of BRCA1 and BRCA2.

Integration of virtual screening of phytoecdysteroids as androgen receptor inhibitors by 3D-QSAR Model, CoMFA, molecular docking and ADMET analysis: An extensive and interactive machine learning.

Ecdysteroids, a class of naturally isolated polyhydroxylated sterols, stands at a very good place in the pharmaceutical industry from their medicinal point of views like anti-inflammatory, neuroprotective, anti-microbial, anti-diabetic, antioxidant, and anti-tumor effects. Due to their excellent antioxidant and anti-microbial potential, ecdysteroids have extensive use in skin products, especially derma creams. To monitor the best anti-acne phytoecdysteroids, here made use of different computational approaches, by using the rapid, easy, cost-effective and high throughput method to screen and identify ecdysteroids as androgen receptor inhibitors. 3D-QSAR study was carried out on a dataset of ecdysteroids by using comparative molecular field analysis (CoMFA) to determine the factors responsible for the activity of compounds. Statistically a cross-validated (q2) 0.1457 and regression coefficient (r2) 0.9713 indicated the best model. Contour map results showed the influence of steric effect to enhance activity. A molecular docking analysis was done to further find out the binding sites and their anti-acne potential against three crystal structured macromolecules (PDB ID: 2REQ, 2BAC, 4EM0). Docking results were further evaluated by prime MM-GBSA analysis and findings confirmed the accuracy. Toxicity by ADMET assessment was carried out and M2 was found as lead druglike with best anti-acne activity against Propionium acnes GehA lipase bacteria after passing all filters. This research study is novel because it is representing first effort to explore ecdysteroids class for their high therapeutic output as androgen receptor inhibitor by using computational tools and expectedly led to novel scaffold for androgen receptor inhibitor. This is a novel and new approach to investigate the ecdysteroids for first time for their practical applications.

Population pharmacokinetics of ciprofloxacin in newborns with early onset neonatal sepsis and suspected meningitis.

BACKGROUND: Neonatal Sepsis accounts for significant proportion of neonatal mortality globally. Ciprofloxacin can be used as an effective antimicrobial against common causative agents of neonatal sepsis. However, there is only limited information about its pharmacokinetic distribution in plasma and Cerebrospinal fluid (CSF) of neonates. METHODS: Plasma and CSF samples were taken using a sparse sampling technique from neonates who received at least one dose of intravenous ciprofloxacin. Ciprofloxacin levels were analysed using high-performance liquid chromatography (HPLC). Population pharmacokinetic analysis was conducted using a non-linear mixed-effects modelling using Pumas® (Pharmaceutical Modelling and Simulation) package (Version 2.0). RESULTS: 53 neonates were enroled in the study of whom; 9 (17%) had meningitis. The median concentration of ciprofloxacin in CSF was 1.4 (0.94-2.06) ug/ml and plasma was 2.94 (1.8-5.0) ug/ml. A one-compartment model with first-order elimination fitted the data. Body weight was found to be a significant covariate on volume of distribution (Vd). Simulations based on the final model suggest that dose of 10 mg/kg, intravenous b.d may not be able to achieve the desirable indices. CONCLUSIONS: One compartment model with weight as a covariate explained the available data. Further studies with modified sampling strategy, larger sample size and variable dose levels are needed.

Developmental landscape of computational techniques to explore the potential phytochemicals from Punica granatum peels for their antioxidant activity in Alzheimer's disease.

Alzheimer's disease (AD) is more commonly found in women than in men as the risk increases with age. Phytochemicals are screened in silico from Punica granatum peels for their antioxidant activity to be utilized for Alzheimer's disease. Alzheimer's disease is inhibited by the hormone estrogen, which protects the brain from the bad effects of amyloid beta and acetylcholine (ACh), and is important for memory processing. For the purpose, a library of about 1,000 compounds from P. granatum were prepared and studied by applying integrated computational calculations like 3D-QSAR, molecular docking, MD simulation, ADMET, and density functional theory (DFT). The 3D-QSAR model screened the active compounds B25, B29, B35, B40, B45, B46, B48, B61, and B66 by the field points and activity atlas model from the prepared library. At the molecular level, docking was performed on active compounds for leading hit compounds such as B25 and B35 that displayed a high MolDock score, efficacy, and compatibility with drug delivery against the antioxidant activity. Optimization of the structure and chemical reactivity parameter of the hit compound was calculated by DFT. Moreover, ADMET prediction was evaluated to check the bioavailability and toxicity of the hit compound. Hesperidin (B25) is found to be a hit compound after the whole study and can be synthesized for potent drug discovery in the future.

Exploration of phenolic acid derivatives as inhibitors of SARS-CoV-2 main protease and receptor binding domain: potential candidates for anti-SARS-CoV-2 therapy.

Severe acute respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the etiological virus of Coronavirus Disease 2019 (COVID-19) which has been a public health concern due to its high morbidity and high mortality. Hence, the search for drugs that incapacitate the virus via inhibition of vital proteins in its life cycle is ongoing due to the paucity of drugs in clinical use against the virus. Consequently, this study was aimed at evaluating the potentials of natural phenolics against the Main protease (Mpro) and the receptor binding domain (RBD) using molecular modeling techniques including molecular docking, molecular dynamics (MD) simulation, and density functional theory (DFT) calculations. To this end, thirty-five naturally occurring phenolics were identified and subjected to molecular docking simulation against the proteins. The results showed the compounds including rosmarinic acid, cynarine, and chlorogenic acid among many others possessed high binding affinities for both proteins as evident from their docking scores, with some possessing lower docking scores compared to the standard compound (Remdesivir). Further subjection of the hit compounds to drug-likeness, pharmacokinetics, and toxicity profiling revealed chlorogenic acid, rosmarinic acid, and chicoric acid as the compounds with desirable profiles and toxicity properties, while the study of their electronic properties via density functional theory calculations revealed rosmarinic acid as the most reactive and least stable among the sets of lead compounds that were identified in the study. Molecular dynamics simulation of the complexes formed after docking revealed the stability of the complexes. Ultimately, further experimental procedures are needed to validate the findings of this study.

Plant-Based Bioactive Phthalates Derived from Hibiscus rosa-sinensis: As In Vitro and In Silico Enzyme Inhibition.

Hibiscus rosa-sinensis is an attractive, ever-blossoming, and effortlessly available plant around the globe. The fabulous flowers of H. rosa-sinensis enjoy a significant status in folk medicine throughout the world and comprise a range of phyto constituents due to which this splendid flower owns numerous biological and pharmaceutical activities like antioxidant, antifungal, antimicrobial, anti-inflammatory, antipyretic, antidiabetic, and antifertility activity. Considering this, column chromatographic isolation of the phytoconstituents of ethyl acetate fraction of the flowers of H. rosa-sinensis was performed. A series of five phthalates including Di-n-octyl phthalate (HR1), ditridecyl phthalate (HR2), 1-allyl 2-ethyl phthalate (HR3), diethyl phthalate (HR4), and bis (6-methylheptyl) phthalate (HR5) were isolated. The structures of the isolated phthalates were elucidated by gas chromatography-mass spectrometry, 1H NMR, and 13C NMR. In silico and in vitro antidiabetic and antioxidant potential and DFT studies of isolated phthalates were carried out. In our study, isolated ligands were explored as potent antidiabetic as well as antioxidant agents as they exhibited good binding affinity (in in vitro and in silico experiments) against all selected protein targets. Compounds HR1-HR5 showed that the binding affinity value ranged from -5.9 to -5.2 kcal/mol, -5.5 to -4.3 kcal/mol, and -5.0 to -4.1 kcal/mol for target proteins 1HNY, 2I3Y, and 5O40, respectively. Among all isolated phthalates, HR5 can be a lead compound as it showed the best binding affinity with human pancreatic α-amylase (ΔG = -5.9 kcal/mol) and displayed a minimum inhibition concentration (IC50) of 11.69 µM among all phthalates. Compound HR1 was the best docked and scored compound for inhibiting glutathione peroxidase; however, HR2 possessed the lowest binding score of -5.0 kcal/mol, thus indicating the highest potential among isolated phthalates for inhibiting the superoxide dismutase. Furthermore, the top-ranked docked ligand-protein complex for each protein was assessed for stability of protein and complex mobility by molecular dynamics simulation using the IMOD server.

Bio-evaluation of poly(lactic-co-glycolic) acid nanoparticles loaded with radiolabelled rifampicin.

AIMS: The poly(lactic-co-glycolic) acid (PLGA) nanoparticles of tubercular drugs have been demonstrated to have a sustained release profile over 7 days. There is no information on the location or mode of release of these nanoparticles in living systems. Therefore, we have planned the study to explore the pharmacokinetics and biodistribution of PLGA rifampicin nanoparticles in healthy human volunteers. We aim to study the distribution pattern of PLGA-loaded nano-formulation of radiolabelled rifampicin in humans. METHODS: Rifampicin was labelled with 99m Tc by indirect method and nanoparticles were prepared by a single emulsion evaporation method. To investigate the pharmacokinetics and biodistribution of nanoparticles, a single dose of 450 mg of rifampicin was administered orally to healthy human volunteers divided into two different groups. RESULTS: Following a single oral dosage of the rifampicin nanoformulation, the pharmacokinetic (PK) parameters were significantly different between the nanoparticle and conventional groups: area under the concentration-time curve (AUC = 113.8 vs. 58.6; P < .001), mean residence time (MRT = 16.2 vs. 5.8; P < .01) and elimination rate constant (Ke = 0.04 vs. 0.10; P < .05). Also, Single-photon emission computed tomography/computed tomography (SPECT/CT) images revealed biodistribution of nanoparticles in the distal portions of the intestine, which is consistent with our dosimetry analysis. CONCLUSIONS: Significant difference in PK parameters and biodistribution of nanoparticles in spleen and lymph nodes with maximum deposition were observed in the large intestine. The nanoparticle distribution pattern may be advantageous for the treatment of intestinal or lymph node tuberculosis (TB) and has the potential to result in a lower dose of rifampicin nanoformulation for the treatment of pulmonary TB.

The combination of multi-approach studies to explore the potential therapeutic mechanisms of imidazole derivatives as an MCF-7 inhibitor in therapeutic strategies.

Breast cancer covers a large area of research because of its prevalence and high frequency all over the world. This study is based on drug discovery against breast cancer from a series of imidazole derivatives. A 3D-QSAR and activity atlas model was developed by exploring the dataset computationally, using the machine learning process of Flare. The dataset of compounds was divided into active and inactive compounds according to their biological and structural similarity with the reference drug. The obtained PLS regression model provided an acceptable r 2 = 0.81 and q2 = 0.51. Protein-ligand interactions of active molecules were shown by molecular docking against six potential targets, namely, TTK, HER2, GR, NUDT5, MTHFS, and NQO2. Then, toxicity risk parameters were evaluated for hit compounds. Finally, after all these screening processes, compound C10 was recognized as the best-hit compound. This study identified a new inhibitor C10 against cancer and provided evidence-based knowledge to discover more analogs.

Exploring the potential of FDA approved anti-diabetic drugs for repurposing against COVID-19: a core combination of multiple computational strategies and integrated artificial intelligence.

The latest variant of coronavirus is omicron. The World Health Organization (WHO) designated variation 'B.1.1.529' named omicron as a variant of concern (VOC) on 26 November 2021. By September 2020, it will have infected over 16 million patients and killed over 600,000 people over the world. This very infectious viral illness still poses a danger to world health; it has also become the greatest problem the world is facing and become the main area of research. The development of vaccines is insufficient to stop their spread and serious effects. Despite several reputable pharmaceutical firms claiming to have developed a cure for COVID-19. For that purpose, the field-based 3D-QSAR model has been used to analyze a series of anti-diabetic drugs to repurpose them against COVID-19. The LOO verified partial least square (PLS) model generates satisfactory q2 (0.4) and r2 (0.5) values. By using this model 10 compounds were screened out of 55 FDA approved anti-diabetic drugs (built-up library). Additionally, these substances were examined using molecular docking screening and ADMET. Finally, the drugs L8, and L23 were discovered to be the lead drugs. Density functional theory at the B3LYP/6-311G* technique was used to examine structural geometries, electronic characteristics, and molecular electrostatic potential (MEP). This work will greatly assist in the detection and development of leads for early drug development to control COVID-19.Communicated by Ramaswamy H. Sarma.

One-pot multicomponent synthesis of novel pyridine derivatives for antidiabetic and antiproliferative activities.

Background: Due to the close relationship of diabetes with hypertension reported in various research, a set of pyridine derivatives with US FDA-approved drug cores were designed and integrated by artificial intelligence. Methods: Novel pyridines were designed and synthesized. Compounds MNS-1-MNS-4 were evaluated for their structure and were screened for their in vitro antidiabetic (α-amylase) activity and anticancer (HepG2) activity by methyl thiazolyl tetrazolium assay. Comparative 3D quantitative structure-activity relationship analysis and pharmacophore generation were carried out. Results: The study revealed MNS-1 and MNS-4 as good alternatives to acarbose as antidiabetic agents, and MNS-2 as a more viable, better alternative to doxorubicin in the methyl thiazolyl tetrazolium assay. Conclusion: This combination of studies identifies new and more active analogs of existing FDA-approved drugs for the treatment of diabetes.