Absorption, Distribution, Metabolism And Excretion Research Articles

Multifaceted investigation of Sulfamerazine: Insights from computational methods, experimental techniques, and molecular simulations

The powerful sulfonamide antibiotic Sulfamerazine has been the subject of in-depth study to clarify its complex molecular interactions. In order to understand Sulfamerazine's pharmacological behaviour and interactions with biological components, this comprehensive study uses computational tools such as Density Functional Theory (DFT) calculations, spectroscopic analyses, and molecular docking simulations. Exploitation B3LYP/6-311++G(d,p) basis set, DFT simulations have provided important new understandings of the structure, vibrational properties, and binding mechanisms of this system. Vibrational assignments have been conducted by analyzing individual vibrational modes and comparing them to experimental data. The molecule's weak interactions have been identified grounded on electron density using Reduced Density Gradient Analysis. Fukui and MEP plot analyses have been employed to pinpoint the molecule's electrophilic and nucleophilic sites. Frontier molecular orbital analysis supported the observation of charge transfer within the molecule. Sulfamerazine is a viable option for further pharmaceutical development, as shown by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) studies. In docking analysis, the inhibitor 6qzh stood out as particularly potent, capable of forming up to three hydrogen bonds, resulting in a binding energy of -8.2 kcal/mol. Molecular dynamics simulations have also shed light on the stability, solubility, and possible interactions of Sulfamerazine in diverse settings. This all-encompassing strategy promises to increase our understanding of the mechanism of action of Sulfamerazine, creating new opportunities for the logical development of more potent pharmaceuticals.

Crystal structure, DFT calculation, molecular docking, in vitro biological activity evaluation and in silico drug-likeness prediction of N-((1H-indol-3-yl)methyl)-4-(piperidin-1-yl)aniline

In the thesis, a novel compound named N-((1H-indol-3-yl)methyl)-4-(piperidin-1-yl)aniline (compound C3) targeting Mycobacterium tuberculosis cyt-bd oxidase was synthesized and crystallized. Compound C3 exhibited significant activity against cyt-bd oxidase, with IC50 values of 26.63 ± 0.2 μM, and also demonstrated efficacy against MtbH37Ra, with MIC values of 16.28 ± 0.2 μM. Therefore, further research was carried out to explore the molecular structure of compound C3 and its interaction with cyt-bd oxidase. Firstly, quantum chemical calculations were carried out to predict various spectral properties of C3 including structural optimization, infrared, Raman, 1H-NMR and 13C-NMR. In addition, Hirshfeld surface analysis is used to clarify the multiple interactions of C3, while two-dimensional fingerprints can accurately quantify the intermolecular interactions. Molecular electrostatic potential (MEP) is used to determine the sites where electrostatic interactions can be formed. Furthermore, FMOs (Frontier Molecular Orbitals) were utilized to assess the chemical stability of C3. Finally, molecular docking research was carried out to study the detailed interactions between cyt-bd oxidase and compound C3. In addition, ADME (absorption, distribution, metabolism and excretion) predictions show that compound C3 has good drug-forming and pharmacokinetics characteristics.

SYSTEMATIC SCREENING OF SYNTHETIC ORGANOCHALCOGEN COMPOUNDS WITH ANTICANCER ACTIVITY USING HUMAN LUNG ADENOCARCINOMA SPHEROIDS

Lung adenocarcinoma stands as a leading global cause of cancer-related fatalities, with current therapeutic approaches remaining unsatisfactory. Given the association between elevated oxidative markers and the aggressive nature of cancer cells (including multidrug resistance and metastatic potential) that can predict poor outcome of lung adenocarcinoma patients, any compounds that interfere with their aberrant redox biology should be rationally explored as innovative intervention strategies. This study was designed to screen potential anticancer activities within nine newly synthesized organochalcogen - compounds characterized by the presence of oxygen, sulfur, or selenium elements in their structure and exhibiting antioxidant activity - and systematically evaluated their performance against cisplatin, the cornerstone therapeutic agent for lung adenocarcinoma. Our methodology involved the establishment of optimal conditions for generating single tumor spheroids using A549 human lung adenocarcinoma cell line. The initiation interval for spheroid formation was determined to be four days in vitro (DIV), and these single spheroids demonstrated sustained growth over a period of 20 DIV. Toxic dose-response curves were subsequently performed for each compound after 24 and 48 hours of incubation at the 12nd DIV. Our findings reveal that at least two of the synthetic organochalcogen compounds exhibited noteworthy anticancer activity, surpassing cisplatin in key parameters such as lower LD (Lethal Dose) 50, larger drug activity area, and maximum amplitude of effect, and are promising drugs for futures studies in the treatment of lung adenocarcinomas. Physicochemical descriptors and prediction ADME (absorption, distribution, metabolism, and excretion) parameters of selected compounds were obtained using SwissADME computational tool; Molinspiration server was used to calculate a biological activity score, and possible molecule targets were evaluated by prediction with the SwissTargetPrediction server. This research not only sheds light on novel avenues for therapeutic exploration but also underscores the potential of synthetic organochalcogen compounds as agents with superior efficacy compared to established treatments.

Identification of small molecule inhibitors against Lin28/let-7 to suppress tumor progression and its alleviation role in LIN28-dependent glucose metabolism.

The reciprocal suppression of an RNA-binding protein LIN28 (human abnormal cell lineage 28) and miRNA Let-7 (Lethal 7) is considered to have a prime role in hepatocellular carcinoma (HCC). Though targeting this inhibition interaction is effective for therapeutics, it causes other unfavorable effects on glucose metabolism and increased insulin resistance. Hence, this study aims to identify small molecules targeting Lin28/let-7 interaction along with additional potency to improve insulin sensitivity. Of 22,14,996 small molecules screened by high throughput virtual screening, 6 molecules, namely 41354, 1558, 12437, 23837, 15710, and 8319 were able to block the LIN28 interaction with let-7 and increase the insulin sensitivity via interacting with PPARγ (peroxisome proliferator-activated receptors γ). MM-GBSA (Molecular Mechanics-Generalized Born Surface Area) analysis is used to re-score the binding affinity of docked complexes. Upon further analysis, it is also seen that these molecules have superior ADME (Absorption, Distribution, Metabolism, and Excretion) properties and form stable complexes with the targets for a significant period in a biologically simulated environment (Molecular Dynamics simulation) for 100 ns. From our results, we hypothesize that these identified 6 small molecules can be potential candidates for HCC treatment and the glucose metabolic disorder caused by the HCC treatment.

Design, Synthesis and In Silico Molecular Docking Evaluation of New Series of 1,2,3‐Triazole Derivatives as Potent Antimicrobial Agents

AbstractChalcone and triazole scaffolds have demonstrated a crucial role in the advancement of science and technology. Due to their significance, research has proceeded on the design and development of novel benzooxepine connected to 1,2,3‐triazolyl chalcone structures. The new chalcone derivatives produced by benzooxepine triazole methyl ketone and different aromatic carbonyl compounds. Product structures were established by various spectral techniques such as IR, 1H NMR, 13C NMR, and mass specrometric analysis. Among the tested compounds, two compounds exhibited exceptional antibacterial susceptibilities with MIC (Minimum inhibitory concentration) range of 3.59–10.30 μM against the tested S. aureus strain. Few of the compounds displayed superior antifungal activity against F. oxysporum with MIC value range from 3.25‐4.89 μM, when compared to fluconazole (MIC=3.83 μM). In addition, few derivatives demonstrated equivalent antitubercular action against H37Rv strain with MIC range of 2.16–4.90 μM. The capacity of one of the ligand to form a stable compound on the active site of CYP51 from M. tuberculosis (1EA1) was confirmed by docking studies. Additionally, the chalcone‐1,2,3‐triazole hybrids ADME (absorption, distribution, metabolism, and excretion), molecular characteristics, estimation of toxicity, and bioactivity scores were assessed.

Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling

ABSTRACT Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

Design, synthesis and in silico molecular docking evaluation of novel 1,2,3-triazole derivatives as potent antimicrobial agents

Chalcone and triazole scaffolds have demonstrated a crucial role in the advancement of science and technology. Due to their significance, research has proceeded on the design and development of novel benzooxepine connected to 1,2,3-triazolyl chalcone structures. The new chalcone derivatives produced by benzooxepine triazole methyl ketone 2 and different aromatic carbonyl compounds 3 are discussed in this paper. All prepared compounds have well-established structures to a variety of spectral approaches, including mass analysis, 1H NMR, 13C NMR, and IR. Among the tested compounds, hybrids 4c, 4d, 4i, and 4k exhibited exceptional antibacterial susceptibilities with MIC range of 3.59–10.30 μM against the tested S. aureus strain. Compounds 4c, 4d displayed superior antifungal activity against F. oxysporum with MIC 3.25, 4.89 μM, when compared to fluconazole (MIC = 3.83 μM) respectively. On the other hand, analogues 4d, 4f, and 4k demonstrated equivalent antitubercular action against H37Rv strain with MIC range of 2.16–4.90 μM. The capacity of ligand 4f to form a stable compound on the active site of CYP51 from M. tuberculosis (1EA1) was confirmed by docking studies using amino acids Leu321(A), Pro77(A), Phe83(A), Lys74(A), Tyr76(A), Ala73(A), Arg96(A), Thr80(A), Met79(A), His259(A), and Gln72(A). Additionally, the chalcone‒1,2,3‒triazole hybrids ADME (absorption, distribution, metabolism, and excretion), characteristics of molecules, estimations of toxicity, and bioactivity parameters were assessed.

Biological New Targets Prediction & ADME Pharmacokinetics Profiling of Newly Synthesized E / Z Isomers of Methyl 2-phenyl-2-(2-phenylhydrazono) Acetate Derivatives

Objective: In order to predict the pharmacokinetic properties, and new potential biological targets, biological targets prediction, and absorption, distribution, metabolism and excretion (ADME) profiling of newly synthesized Entgegen / Zusammen (E / Z isomers) of Methyl 2-phenyl-2-(2-phenylhydrazono) acetate derivatives were carried out. Methods: The prediction of new biological targets, pharmacokinetic properties, membrane permeability, and bioavailability radar properties were carried out by using Swiss Targets Prediction and Swiss ADME tools, respectively. Results: All the eight screened compounds possessed excellent drug-likeness criteria and passed successfully from Pan-assay interference compounds filter. Additionally, all screened compounds fell within the acceptable range in the bioavailability radar, showing excellent descriptors with a slight exceeding of insaturation properties. Compounds displayed elevated permeability across the Blood Brain Barrier, while compounds exhibited highest Human Intestinal Absorption according to the Egan Egg model. Moreover, the screened compounds also exhibited good pharmacokinetic properties. All the compounds exhibited activity against various enzymes, such as lyase, kinase, protease, and Family AG protein-coupled receptor. Conclusion: This conducted study smartly reveals that in-silico based studies were considered to provide robustness towards a rational drug design and development approach; therefore, in this way, it helps for further investigation of drug design and drug discovery steps.

New N-(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors

Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II (hCA I and hCA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by 1H NMR,13C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against hCA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against hCA II, except for compounds 5b and 6b. Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure–activity relationship. Communicated by Ramaswamy H. Sarma

Solubility and Stability of Carvedilol in Deep Eutectic Solvents: A Step Towards a Sustainable Pharmaceutical Formulation in the Liquid State

AbstractCarvedilol is used to treat chronic hypertension, chronic stable angina pectoris and concomitant treatment heart failure and class II of the Biopharmaceutics Classification System (low solubility and poor bioavailability). This drug is only formulated as tablets, and liquid oral formulations are not available on the market. In this work, several aqueous eutectic mixtures formed by xylitol, citric acid, sorbitol and glucose (HBD) and choline chloride as HBA have been used to improve the solubility. Additionally, SwissADME was used to obtain physicochemical and pharmacokinetic parameters to further knowledge on the ADME (absorption, distribution, metabolism and excretion) parameters for carvedilol.The results reveal that the solubility of carvedilol increases as the content of water decreases, and the mixture formed by citric acid and choline chloride (CACh10) was the most soluble. The stability study shows that carvedilol in DES is stable during the test time, as the maximum and minimum concentration losses were 19.0 % and 0.2 %, respectively. These results help advance the green and sustainable development of new medicines in the liquid state.

Antiplasmodial activity, in silico ADME and mammalian cell cytotoxicity of a synthetic protoberberine alkaloid, coralyne

Coralyne is a synthetic protoberberine alkaloid with anticancer activity and selectivity superior to that of berberine, its congener. As berberine is gifted with antiplasmodial activity, this study assessed the antiplasmodial activity of coralyne against erythrocytic stages of the malaria parasite in culture. Parasites were cultured by adopting the method described by Trager and Jensen in 1976. Following this, parasites were exposed at ring stage to increasing doses of coralyne to enable us compute the IC50. Further, given that berberine is a substrate of the efflux transporter permeability glycoprotein (P-gp), in silico techniques were used to study the pharmacokinetics of oral coralyne. Coralyne showed excellent potency (IC50Pf3D7: 0.52 µg/ml) against chloroquine sensitive strain and a little less potency (IC50PfINDO: 1.15 µg/ml) against the chloroquine resistant malaria parasite strain (Resistance index: 2.21). Further, with CC50HEK: >100 µg/ml, it was non-toxic to mammalian cells. However, in silico absorption, distribution, metabolism and excretion (ADME) studies predicts that like berberine, coralyne may also have poor oral bioavailability thus limiting its usefulness as an orally deliverable antimalarial agent. Given the negative impact of low bioavailability in the development of protoberberine alkaloids as antimalarials, synthesizing analogues of coralyne with nanomolar potency against the malaria parasite and improved oral pharmacokinetics may be a good strategy for the future.

Nootropic Property of Punica grantum Extract as BDNF4 Stimulant for Treatment of Major Depressive Disorder

In 2008, the World Health Organization (WHO) stressed major depressive disorder (MDD) as the third most important cause of disease burden worldwide. Based on their projections, it is expected that by 2030, MDD will take the lead among the rest of the world’s health concerns. Brain derived neurotrophic factor 4 (BDNF4), a protein of neurotrophins family play pivotal role in maintaining neural plasticity, and its reduced level in the hippocampus and plasma have been reported in patients with MDD. Nootropic drugs serve as therapeutic interventions in mitigating MDD through diverse molecular mechanisms. Punica granatum (pomegranate) is acknowledged for its nutritional and medicinal properties, currently under medical scrutiny for its potential as a natural antidepressant. Various computational methodologies, including molecular docking, pharmacokinetics, ADME (absorption, distribution, metabolism and excretion) profile assessment, toxicological analysis, and prediction of biological activity, were employed to identify promising compounds among the phytochemicals present in Punica extract, focusing on their potential BDNF4-stimulating, nootropic, and antidepressant properties. The comprehensive examination of docking scores, interactions between proteins and ligands, pharmacological and toxicological attributes, along with the forecasting of biological activities, collectively underscores the potential attributes of M-Cymene, Flavylium, 2-(4-Methylphenyl)propan-2-ol, Thymol, and Pelletierine as prospective drug candidates targeting human BDNF4 for alleviating MDD.

Identification of Hsp90 inhibitors from Ananas comosus potential phytochemicals for lung cancer treatment

Lung cancer is a significant global health issue, with thousands of lives lost each year. One potential approach to preventing lung cancer is the use of heat shock protein 90 (Hsp90) inhibitors, which have been shown to induce substantial cell death in both chemo-sensitive and chemo-resistant small cell lung cancer cells. In this study, we conducted in silico computational molecular docking of pineapple phytochemicals with Hsp90 to investigate their potential inhibitory effects on Hsp90 and, consequently, their ability to prevent lung cancer. Our findings demonstrate that the phytochemicals found in Ananas comosus, specifically caffeic acid, ferulic acid, 4-Hydroxycinnamic acid, Sinapic acid, and D-Galacturonic Acid, exhibit notable inhibitory activity against Hsp90. Beyond their Hsp90 inhibition, these phytochemicals also demonstrate promising biological activities, serving as effective agents against neoplastic conditions, particularly lung cancer, and displaying pro-apoptotic properties. Moreover, the ADME (Absorption, Distribution, Metabolism, and Excretion) and toxicological assessments conducted on these compounds yielded satisfactory results. These findings suggest that pineapple phytochemicals may have potential in the development of novel therapeutic strategies for lung cancer prevention.

Analysis of pharmacokinetic profile and ecotoxicological character of cefepime and its photodegradation products

An important problem is the impact of photodegradation on product toxicity in biological tests, which may be complex and context-dependent. Previous studies have described the pharmacology of cefepime, but the toxicological effects of its photodegradation products remain largely unknown. Therefore, photodegradation studies were undertaken in conditions similar to those occurring in biological systems insilico, in vitro, in vivo and ecotoxicological experiments. The structures of four cefepime photodegradation products were determined by UPLC-MS/MS method. The calculated in silico ADMET profile indicates that carcinogenic potential is expected for compounds CP-1, cefepime, CP-2 and CP-3. The Cell Line Cytomotovity Predictor 2.0 tool was used to predict the cytotoxic effects of cefepime and related compounds in non-transformed and cancer cell lines. The results indicate that possible actions include: non-small cell lung cancer, breast adenocarcinoma, prostate cancer and papillary renal cell carcinoma. OPERA models were used to predict absorption, distribution, metabolism and excretion (ADME) endpoints, and potential bioactivity of CP-2, cefepime and CP-4. The results obtained in silico show that after 96h of exposure, cefepime, CP-1, CP-2, and CP-3 are moderately toxic in the zebrafish model, while CP-4 is highly toxic. On the contrary, cefepime is more toxic to T. platyurus (highly toxic) compared to the zebrafish model, similar to products CP-4, CP-3 and CP-2. In vitro cytotoxicity studies were performed by MTT assay and in vivo acute embryo toxicity studies using Danio rerio embryos and larvae. In vitro showed an increase in the cytotoxicity of products with the longest exposure period i.e. for 8 h. Additionally, at a concentration of 200 μg/mL, statistically significant changes in metabolic activity were observed depending on the irradiation time. In vivo studies conducted with Zebrafish showed that both cefepime and its photodegradation products have only low toxicity. Assessment of potential ecotoxicity included Microbiotests on invertebrates (Thamnotoxkit F and Daphtoxkit F), and luminescence inhibition tests (LumiMara). The observed toxicity of the tested solutions towards both Thamnocephalus platyurus and Daphnia magna indicates that the parent substance (unexposed) has lower toxicity, which increases during irradiation. The acute toxicity (Lumi Mara) of nonirradiated cefepime solution is low for all tested strains (<10%), but mixtures of cefepime and its photoproducts showed growth inhibition against all tested strains (except #6, Photobacterium phoreum). Generally, it can be concluded that after UV–Vis irradiation, the mixture of cefepime phototransformation products shows a significant increase in toxicity.

Biochemical and in silico analysis of the binding mode of erastin with tubulin

Erastin (ERN) is a small molecule that induces different forms of cell death. For example, it has been reported to induce ferroptosis by disrupting tubulin subunits that maintain the voltage-dependent anion channels (VDACs) of mitochondria. Although its possible binding to tubulin has been suggested, the fine details of the interaction between ERN and tubulin are poorly understood. Using a combination of biochemical, cell-model and in silico approaches, we elucidate the interactions of ERN with tubulin and their biological manifestations. After confirming ERN's antiproliferative efficacy (IC50, 20 ± 3.2 M) and induction of cell death in the breast cancer cell line MDA-MB-231, the binding interactions of ERN with tubulin were examined. ERN bound to tubulin in a concentration-dependent manner, disorganizing the structural integrity of the protein, as substantiated via the tryptophan-quenching assay and the aniline-naphthalene sulfonate binding assay, respectively. In silico studies based on molecular docking revealed a docking score of −5.863 kcal/mol, suggesting strong binding interactions of ERN with tubulin. Additionally, molecular dynamics simulation and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) analyses evinced the binding free energy (ΔGbinding) of −31.235 kcal/mol, substantiating strong binding affinity of ERN with tubulin. Ligplot analysis showed hydrogen bonding with specific amino acids (Asn A226, Thr A223, Gln B247 and Val B355). QikProp-based ADME (absorption, distribution, metabolism and excretion) assessment showed considerable therapeutic potential for ERN. Communicated by Ramaswamy H. Sarma

Use of hybrid molecular simulation techniques for systematic analysis of polyphenols as promising therapeutic agent against SARS-CoV-2

In our current study, we systematically report the four phenol classes via three-layer in silico screening approaches consisting of quantum chemical methods, molecular docking and molecular dynamics simulations. We studied the interactions of main protease (Mpro) and Nsp9 proteins of SARS-CoV-2 with four classes of polyphenolic compounds, where both proteins are crucial for virus replication. The phenols are extensively reported for medicinal applications, as these are antioxidants, anti-parasitic, anti-viral, anti-diabetic and anti-inflammatory compounds. Initial molecular docking study shows that among forty phenolic compounds the L9, L17, L26 and, L32 reveal the best binding energies with Mpro protein. Their values of docking score in terms of binding energy with Mpro protein is ranging from -5.7 to -6.8 kcal.mol−1. While on the other hands, L8, L11, L22 and, L34 exhibit the best docking scores with Nsp9 protein, which are ranging from -5.8 to -6.8 kcal.mol−1. Additionally, the lead compounds (ligands) were studied by quantum chemical methods for their optimized or the lowest energy structures, electronic properties, frontier molecular orbitals (FMOs) as well as molecular electrostatic potentials (MEPs). The global chemical descriptors are also calculated to explain the global reactivity trend for the lead compounds. To mimic the aqueous like environment, we added ions according to the electrostatic potential of the macromolecule, water molecules are being added to create physiologically relevant environment for studying biological molecules. Proteins, nucleic acids, and other biomolecules are typically surrounded by water molecules in biological systems. The addition of water molecules in MD simulations may provide a more accurate representation of their natural environment. The molecular dynamics simulations are performed for the complexes of best-docked lead compounds and for both proteins (Mpro and, Nsp9) over multiple replicate trajectories of 320 ns. The flexibility and stability behavior of the lead compounds in terms of RMSD and RMSF plots are analyzed through MD simulations results. The binding free energy of the best-docked lead compounds with both proteins in terms of Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis are calculated, which are found as -8.79 and -3.97 kcal.mol−1 for Mpro-L32 and Nsp9-L8 complexes, respectively. The pharmacokinetic analysis of the lead compounds are also performed to disclose their ADME (absorption, distribution, metabolism, and excretion) and toxic character using online server pkCSM. This allowed for a comprehensive understanding of how these compounds would behave in the organism, specifically focusing on their ADME properties. We believe that the current study can evoke the interest of scientific community by providing fundamental insights, which will ultimately lead in-vivo and in-vitro analysis to assess the studied phenolic therapeutic inhibitors against the SARS-CoV-2.

Two rare flavonoid glycosides from Litsea glutinosa (Lour.) C. B. Rob.: experimental and computational approaches endorse antidiabetic potentiality

BackgroundLitsea glutinosa (Lour.) C. B. Rob. belongs to the Litsea genus and is categorized under the family of Lauraceae. The study aimed to investigate the phytoconstituents and pharmacological properties of methanol extract of leaves of Litsea glutinosa, focusing on antidiabetic activity via in vivo and in silico techniques.MethodsExtensive chromatographic and spectroscopic techniques were applied to isolate and characterize the constituents from the L. glutinosa plant species. The antidiabetic activity was studied in streptozotocin-induced diabetes mice, and the computational study of the isolated compounds was carried out by utilizing AutoDock Vina programs. In addition, the pharmacokinetic properties in terms of absorption, distribution, metabolism and excretion (ADME) and toxicological profiles of the isolated compounds were examined via in silico techniques.ResultsIn the present study, two flavonoid glycosides 4΄-O-methyl (2 ̋,4 ̋-di-E-p-coumaroyl) afzelin (1) and quercetin 3-O-(2 ̋,4 ̋-di-E-p-coumaroyl)-α-L-rhamnopyranoside (2) were isolated from the leaves of L. glutinosa and characterized by 1H and 13C NMR, COSY, HSQC, HMBC, and mass spectral data. Although compounds 1 and 2 have been reported twice from Machilis litseifolia and Lindera akoensis, and Machilis litseifolia and Mammea longifolia, respectively, this is the first report of this isolation from a Litsea species. Administering the methanolic extract of L. glutinosa at doses of 300 and 500 mg/kg/day to mice with diabetes induced by streptozotocin led to a significant decrease in fasting blood glucose levels (p < 0.05) starting from the 7th day of treatment. Besides, the computational study and PASS analysis endorsed the current in vivo findings that the both isolated compounds exerted higher binding affinities to human pancreatic α-amylase and aldose reductase than the conventional drugs. The in silico ADMET analysis revealed that the both isolated compounds have a favorable pharmacokinetic and safety profile suitable for human consumption.ConclusionAccording to the current outcomes obtained from in vivo and in silico techniques, the leaf extract of L. glutinosa could be a natural remedy for treating diabetes, and the isolated phytoconstituents could be applied against various illnesses, mainly hyperglycemia. However, more investigations are required for extensive phytochemical isolation and pharmacological activities of these phytoconstituents against broader targets with exact mechanisms of action.

Computational/In‐Silico Methods: An Influential Approach for Drug Designing and Development

AbstractAs the world is struggling with the pandemic. Various infectious diseases have become a threat to human health. Millions of deaths are caused by these microbial infections (bacterial, fungal, and viral infections). The process of designing and discovering new drugs is very expensive and it also consumes a good amount of time. As per available data, the process of discovery and designing takes 3–20 years to complete. There is a strong urge and demand to discover new methods to make the process of drug design and development more cost‐effective. Computational methods are one the novel methods for designing and developing a drug. In this respect, in‐silico parameters; ADME (Absorption, Distribution, Metabolism, and Excretion) models have been established with various levels of complication for the transmission of huge data of derivatives/ligands/drugs. Nowadays, in‐silico tools are more cost‐effective, faster, and simpler than transitional experimental trials. Currently, the pharmaceutical industry faces a huge erosion rate of preclinical and clinical applicants due to the unavailability of pharmacokinetics properties and huge toxicity. These can be minimized via structural modifications of drugs and can help medicinal chemists/pharmacists. In this report, various methodologies and steps have been explained via molecular docking that will lead to drug development in lesser time against various stains.

An in silico approach to investigate the theranostic potential of coumarin-derived self-immolative luminescent probes.

Till date the challenge exists in the treatments of cancer for various reasons. Most importantly, the available diagnostics are expensive with research gap for enhancing the cancer detection sensitivity. Herein, a series of coumarin-derived fluorescent theranostic probes are reported that can serve as potent anticancer agents as well as in the detection of cancer cells. The potential of these probes to efficiently block one of the well-known cancer drug targets NADPH quinone oxidoreductase-1 (NQO1) is evaluated through various pharmacokinetic methods including absorption, distribution, metabolism and excretion (ADME) properties evaluation, PASS (prediction of activity spectra for substance) algorithm along with molecular docking and dynamic simulations. Further the luminescent properties of these molecules were evaluated by investigating their electronic properties in the ground and excited states with the help of density functional theory methods. Results indicate that the proposed molecules can potentially block the NADPH (reduced form of nicotinamide adenine dinucleotide) binding site of NQO1, thereby inhibiting the activity of the enzyme to ultimately disrupt the metabolism of cancer cells.

Machine learning-guided design of potent darunavir analogs targeting HIV-1 proteases: A computational approach for antiretroviral drug discovery.

In the pursuit of novel antiretroviral therapies for human immunodeficiency virus type-1 (HIV-1) proteases (PRs), recent improvements in drug discovery have embraced machine learning (ML) techniques to guide the design process. This study employs ensemble learning models to identify crucial substructures as significant features for drug development. Using molecular docking techniques, a collection of 160 darunavir (DRV) analogs was designed based on these key substructures and subsequently screened using molecular docking techniques. Chemical structures with high fitness scores were selected, combined, and one-dimensional (1D) screening based on beyond Lipinski's rule of five (bRo5) and ADME (absorption, distribution, metabolism, and excretion) prediction implemented in the Combined Analog generator Tool (CAT) program. A total of 473 screened analogs were subjected to docking analysis through convolutional neural networks scoring function against both the wild-type (WT) and 12 major mutated PRs. DRV analogs with negative changes in binding free energy ( ) compared to DRV could be categorized into four attractive groups based on their interactions with the majority of vital PRs. The analysis of interaction profiles revealed that potent designed analogs, targeting both WT and mutant PRs, exhibited interactions with common key amino acid residues. This observation further confirms that the ML model-guided approach effectively identified the substructures that play a crucial role in potent analogs. It is expected to function as a powerful computational tool, offering valuable guidance in the identification of chemical substructures for synthesis and subsequent experimental testing.