Human Intestinal Absorption Research Articles

In silico and in vitro approaches to evaluate the bioactivities of Chaetomorpha linum

• Marine algae are prolific source of bioactive secondary metabolites and are found to be active against therapeutic agents. • In vitro and insilico antioxidant and anticancer was evaluated by DPPH, TPC and TFC assay, ADMET and Molecular docking. • Excellent antioxidant and anticancer displayed by majority of the extracts. • Enzyme and antioxidant were impressively inhibited by the Chaetomorpha linum ethanol extract Molecular modeling indicated the interaction of chemical constituents with studied enzymes. Seaweeds are rich in bioactive metabolites that could be used to develop new natural compounds in the pharmaceutical and cosmetic industries. The secondary metabolites, antioxidants, ADMET, Molecular docking and anticancer agents are investigated in the present study. The current research shows that seaweed, Chaetomorpha linum is vital source of natural antioxidants, which confirmed by free radical scavenging activity, DPPH, total phenolic and flavonoid content. The enzyme maximum inhibition of Glutathione respectively . It is noteworthy that glucoside action is dominant over the amylase enzyme. The anti-cancer activity of ethanol extracts showed the IC 50 values 72.8 μg/mL −1 for MCF-7, respectively. The identified phytocompound absorption, distribution, metabolism and excretion assessed by SWISS ADME/T, it provides information about Human intestinal absorption and blood–brain barrier permeability. In addition, phytocompounds interaction with protein was confirmed by molecular docking. The protein 3ERT interaction of compounds 3 (-7.97 kcal/mol), compound 4 (-8.36 kcal/mol) and compound 2 (2,4-Di-tert-butylphenol -6.96 kcal/mol) provides high binding energy in comparison to other proteins. Hence, the present studies indicate that antioxidant, anti- diabetic and anticancer activity of ethanol extract as an alternative to the existing therapeutic approach to diabetic and cancer through a systematic in vitro and in silico approaches supplementing the findings.

COMPUTATIONAL DRUG REPROPOSING TO IDENTIFY SARS-COV-2 MPRO INHIBITORS: MOLECULAR DOCKING, ADMET ANALYSIS, AND IN-SILICO/IN-VITRO TOXICITY STUDY

Aim and Objective: After the COVID-19 outbreak, drug repurposing has emerged as an effective and fast approach for combating the SARS-CoV-2 crisis. in this work, computational drug repurposing has been utilized to identify new SARS-CoV-2Mpro inhibitors. Methods: Comparative molecular docking studies were used to evaluate the activity of the commercially available oral antiviral drug simeprevir and its degradation products (compounds 1–5) against the main protease (Mpro)of SARS-CoV-2 (PDB ID: 6lu7; resolution: 2.16 Å). Moreover, the ADMET and in-silico toxicity properties of the acidic (compounds 1–3) and oxidative (compounds 4 and 5) degradation products of simeprevir were predicted. Results: Docking studies revealed good binding affinities for compounds (1–5) against Mpro of SARS-CoV-2, with binding free energies ranging from −6.23 to −7.65 kcal/mol. The acidic degradant 2 exhibited the best affinity and was superior to simeprevir and a natural ligand. All compounds were expected to be safe to the CNS. Conclusion: Compounds 1, 4, and 5 were expected to possess good human intestinal absorption, whereas compounds 2 and 3 appeared to have moderate intestinal absorption. Peer Review History: Received: 1 September 2022; Revised: 11 October; Accepted: 6 November, Available online: 15 November 2022 Academic Editor: Dr. DANIYAN Oluwatoyin Michael, Obafemi Awolowo University, ILE-IFE, Nigeria, toyinpharm@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Gehan Fawzy Abdel Raoof Kandeel, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt, gehankandeel9@yahoo.com Dr. Nicola Micale, University of Messina, Italy, nmicale@unime.it Prof. Cyprian Ogbonna ONYEJI, Obafemi Awolowo University, Ile-Ife, Nigeria, conyeji@oauife.edu.ng Similar Articles: USE OF COLCHICINE TO COUNTERACT THE STRONG HYPERINFLAMMATORY STATE INDUCED BY SARS-COV-2 THE ROLE OF ANTICOAGULANTS AND ANTIPLATELETS IN PROPHYLAXIS AND/OR TREATMENT OF SEVERE SARS-COV-2 INFECTION

Inhibition of the predicted allosteric site of the SARS-CoV-2 main protease through flavonoids

Since its emergence in 2019, coronavirus infection (COVID-19) has become a global pandemic and killed several million people worldwide. Even though several types of vaccines are available against the COVID-19 virus, SARS-CoV-2, new strains are emerging that pose a constant danger to vaccine effectiveness. In this computational study, we identified and predicted potent allosteric inhibitors of the SARS-CoV-2 main protease (Mpro). Via molecular docking and simulations, more than 100 distinct flavonoids were docked with the allosteric site of Mpro. Docking experiments revealed four top hit compounds (Hesperidin, Schaftoside, Brickellin, and Marein) that bound strongly to the Mpro predicted allosteric site. Simulation analyses further revealed that these continually interacted with the enzyme’s allosteric region throughout the simulation time. ADMET and Lipinski drug likenesses were calculated to indicate the therapeutic value of the top four hits: They were non-toxic and exhibited high human intestinal absorption concentrations. These novel allosteric site inhibitors provide a higher chance of drugging SARS-CoV2 Mpro due to the rapid mutation rate of the viral enzyme’s active sites. Our findings provide a new avenue for developing novel allosteric inhibitors of SARS-CoV-2 Mpro. Communicated by Ramaswamy H. Sarma

Molecular Mechanism of Inhibition of Cell Proliferation: An In Silico Study of the Active Compounds in <i>Curcuma longa</i> as an Anticancer

Cancer is one of the death causes in the world. Many plants act as anticancer, one of them is Curcuma longa. The purpose of this study was to analyze the molecular mechanism of compounds in Curcuma longa as an anticancer using in silico. These research methods included exploration of the active compounds of Curcuma longa plants, prediction of their activity, human intestinal absorption test, test of Lipinski's rule of five, molecular docking, and interactions of receptor with compounds as well as signaling pathways. The results showed that Curcuma longa had 20 compounds that have the potential as an anticancer. As many as 5 of the 20 active compounds, namely α-curcumene, curcumenol, curcumin, curcumin II, and curcumin III had a value of Pa > 0.3 and HIA above 80%. The results of molecular docking of α-curcumene, curcumenol, curcumin, curcumin II, and curcumin III compounds with protein receptors of VEGFR-2, EGFR, and FGFR-1 showed ∆Gbind values of -5.0 to -7.5 kcal/mol. The compound in Curcuma longa that had the most effective activity as an anticancer was curcumin with a ∆Gbind value of -7.5 kcal/mol at the FGFR-1 receptor. Curcumin molecular mechanism as antiproliferative was revealed computationally through inhibition of the PI3K/AKT/mTOR pathway.

Design of Amide bioisosteres of Flutamide as Novel Androgen Receptor Antagonist in Prostate Cancer Therapy

Prostate cancer is the second leading cause of cancer death in men. Androgen receptor (AR) inhibitor is one of class of drug used in this disease. AR inhibitors include bicalutamide, flutamide, nilutamide, apalutamide, darolutamide and enzalutamide. Among them Flutamide is being selected because it causes liver damage on long term use that can be serious or life-threatening. In the current study, Bioisosteric approach has been used for amide group in the Flutamide molecule in order to develop the newer analogues having lesser side effects like liver damage, which is major cause of the drug withdrawal. Therefore amide bioisosteres of it are designed using bioisosteric approach in order to develop relatively safe compounds. A wide variety of amide bioisosteres of Flutamide were generated i.e., Ester, Amide, Reverse amide, Urea, Carbamate, Reverse Ester, Thioamide, 1,2,4-oxadiazole, Sulphonamide, Ketone etc., using MolOpt. Pharmacokinetic and toxicity (ADMET) properties of newly designed analogues are computed by using ADMElab2.0 and pkCSM. Druglikeness and Drugscore was calculated by PEO. All the ligands obey the Lipinski rule and had good human intestinal absorption. Flutamide is used as the reference drug. The results indicate that compound 002 and 022 showed NR-AR binding (desirable in Prostate cancer) and QED value (measure of drug likeness; > 0.67) comparable with the standard drug. These compounds showed low toxicity [human hepatotoxicity (H-HT) and drug induced liver injury (DILI)] as compared to Flutamide. This study could lead to the further development of potent AR antagonist for the treatment of prostate cancer.

Protective role of fermented whey and pumpkin extract against aflatoxin B1 and ochratoxin A toxicity in Jurkat T-cells

The beneficial effect of fermented whey and pumpkin extract rich in carotenoids was evaluated in Jurkat cells against aflatoxin B1 (AFB1) and ochratoxin A (OTA) cytotoxicity through a proteomic approach. The functional ingredients were added into mycotoxin contaminated bread formulation, which were digestedin vitro in order to simulate human intestinal absorption. Cell cultures were exposed during 7 days to these mycotoxins dissolved in: (a) 0.1% organic solvent (DMSO), (b) an intestinal digest of bread with pumpkin individually (PID) and (c) an intestinal digest of bread with pumpkin mixed with fermented whey (PID+WF). Extracted proteins were subjected to reduction and alkylation and subsequently a tryptic digestion in order to be analysed by liquid chromatography coupled with quadrupole time of flight (LC/MS-Q-TOF). Results obtained highlighted the beneficial role of functional ingredients employed through the identification of proteins involved in several biological processes and metabolic pathways, mainly antioxidant activity, nucleosome assembly and secretory senescence phenotype. Among proteins involved in antioxidant activity, peroxiredoxin 1 and 2 stand out. Comparing the different conditions investigated, a remarkable change was observed in their expression, ranging from a repression using the standard (DMSO 0.1%), to an overexpression when treated with the functional ingredients. Similarly, after PID and PID+WF treatment, histones’ expression implicated in the metabolic pathway of nucleosome assembly, such as H2A, H2B, H2C, H3 and H4, was increased. Furthermore, the expression of protein cyclin A2, which downregulation is involved in limiting carcinogenic cells growth, was lower in presence of both functional ingredients. Based on these findings, functional ingredients can act as protectors against genomic stress caused by mycotoxins, preventing the loss of vital cell functions and paralysing the growth of carcinogenic cells.

Establishment and Characterization of Novel Human Intestinal In Vitro Models for Absorption and First-Pass Metabolism Studies.

Commonly used intestinal in vitro models are limited in their potential to predict oral drug absorption. They either lack the capability to form a tight cellular monolayer mimicking the intestinal epithelial barrier or the expression of cytochrome P450 3A4 (CYP3A4). The aim of this study was to establish a platform of colorectal cancer patient-derived cell lines for evaluation of human intestinal drug absorption and metabolism. We characterized ten 2D cell lines out of our collection with confluent outgrowth and long-lasting barrier forming potential as well as suitability for high throughput applications with special emphasis on expression and inducibility of CYP3A4. By assessment of the transepithelial electrical resistance (TEER) the cells barrier function capacity can be quantified. Very high TEER levels were detected for HROC60. A high basal CYP3A4 expression and function was found for HROC32. Eight cell lines showed higher CYP3A4 induction by stimulation via the vitamin D receptor compared to Caco-2 cells (5.1- to 16.8-fold change). Stimulation of the pregnane X receptor led to higher CYP3A4 induction in two cell lines. In sum, we identified the two cell lines HROC183 T0 M2 and HROC217 T1 M2 as useful tools for in vitro drug absorption studies. Due to their high TEER values and inducibility by drug receptor ligands, they may be superior to Caco-2 cells to analyze oral drug absorption and intestinal drug–drug interactions. Significance statement: Selecting appropriate candidates is important in preclinical drug development. Therefore, cell models to predict absorption from the human intestine are of the utmost importance. This study revealed that the human cell lines HROC183 T0 M2 and HROC217 T1 M2 may be better suited models and possess higher predictive power of pregnane X receptor- and vitamin D-mediated drug metabolism than Caco-2 cells. Consequently, they represent useful tools for predicting intestinal absorption and simultaneously enable assessment of membrane permeability and first-pass metabolism.

Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists.

New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile.

A proof of concept using the Ussing chamber methodology to study pediatric intestinal drug transport and age-dependent differences in absorption.

Little is known about the impact of age on the processes governing human intestinal drug absorption. The Ussing chamber is a system to study drug transport across tissue barriers, but it has not been used to study drug absorption processes in children. This study aimed to explore the feasibility of the Ussing chamber methodology to assess pediatric intestinal drug absorption. Furthermore, differences between intestinal drug transport processes of children and adults were explored as well as the possible impact of age. Fresh terminal ileal leftover tissues from both children and adults were collected during surgery and prepared for Ussing chamber experiments. Paracellular (enalaprilat), transcellular (propranolol), and carrier‐mediated drug transport by MDR1 (talinolol) and BCRP (rosuvastatin) were determined with the Ussing chamber methodology. We calculated apparent permeability coefficients and efflux ratios and explored their relationship with postnatal age. The success rate for the Ussing chamber experiments, as determined by electrophysiological measurements, was similar between children (58%, N = 15, median age: 44 weeks; range 8 weeks to 17 years) and adults (67%, N = 13). Mean serosal to mucosal transport of talinolol by MDR1 and rosuvastatin by BCRP was higher in adult than in pediatric tissues (p = 0.0005 and p = 0.0091). In contrast, within our pediatric cohort, there was no clear correlation for efflux transport across different ages. In conclusion, the Ussing chamber is a suitable model to explore pediatric intestinal drug absorption and can be used to further elucidate ontogeny of individual intestinal pharmacokinetic processes like drug metabolism and transport.

In Silico Docking Analysis of Anti-malaria and Anti-typhoid Potentials of Phytochemical Constituents of Ethanol Extract of Dryopteris dilatata

Traditional medicinal plants are a possible source of anti-malarial and anti-typhoid medications, and there is growing interest in the usage and development of herbal medicinal therapies for these ailments. The study aims to investigate the anti-malaria and anti-typhoid properties of Dryopteris dilataa leaves in silico. The plant leaves were extracted in ethanol and analyzed using Fourier transform infrared spectrometer (FTIR) and gas chromatography-mass spectrometry (GC–MS). The drug likeness and ADME predictions were done with OSIRIS property explorer and ADMETSAR webserver, while the molecular docking against dehydrogenase (Malaria target) and D-glutamate ligase enzyme (Typhoid Target) was done using Autodock Vina. The FT-IR results indicated the presence of -OH, CH3, C-H aromatic and C=O functional groups while the GC-MS revealed thirteen (13) potential medicinal compounds, nine (9) compounds showed good pharmacokinetic properties having high human intestinal absorption, less toxic and good overall drug score. The  molecular docking study revealed that three compounds, 1,2,3,4,7,8,9,10-Octahydro-12H-[1]benzothieno[2,3-d]pyrido[1,2-a]pyrimidin-12-one (-6.7 Kcal/mol), 4,7,9-Trihydroxy-2-methylnaphtho[2,3-b]furan-5,8-dione (-6.0 Kcal/mol), and 1,2,3-Triazol, 2-(E-4,4-dicyano-3-N-methylanilino-1,3-butadien-1-yl)-4-(methoxycarbonyl) (-6.3 Kcal/mol), gave better score for binding affinity than the control anti-malarial drug artesunate (-5.9 Kcal/mol). The typhoid docking also revealed the compounds, 4,7,9-trihydroxy-2-methylnaphtho[2 ,3-b]furan-5,8-dione (-8.6 Kcal/mol) and 1,2,3-Triazol, 2-(E-4,4-dicyano-3-N-methylanilino-1,3-butadien-1-yl)-4-(methoxycarbonyl)- (−8.3 Kcal/mol) had better binding affinity score than the reference anti-typhoid drug Ciprofloxacin (-8.1Kcal/mol). The research justifies the local claims on the use of the plant and strengthens the relevance of these compounds as promising lead candidates for the treatment of Malaria and typhoid.&nbsp

A Computational Approach Applied to the Study of Potential Allosteric Inhibitors Protease NS2B/NS3 from Dengue Virus.

Dengue virus (DENV) is a danger to more than 400 million people in the world, and there is no specific treatment. Thus, there is an urgent need to develop an effective method to combat this pathology. NS2B/NS3 protease is an important biological target due it being necessary for viral replication and the fact that it promotes the spread of the infection. Thus, this study aimed to design DENV NS2B/NS3pro allosteric inhibitors from a matrix compound. The search was conducted using the Swiss Similarity tool. The compounds were subjected to molecular docking calculations, molecular dynamics simulations (MD) and free energy calculations. The molecular docking results showed that two compounds, ZINC000001680989 and ZINC000001679427, were promising and performed important hydrogen interactions with the Asn152, Leu149 and Ala164 residues, showing the same interactions obtained in the literature. In the MD, the results indicated that five residues, Lys74, Leu76, Asn152, Leu149 and Ala166, contribute to the stability of the ligand at the allosteric site for all of the simulated systems. Hydrophobic, electrostatic and van der Waals interactions had significant effects on binding affinity. Physicochemical properties, lipophilicity, water solubility, pharmacokinetics, druglikeness and medicinal chemistry were evaluated for four compounds that were more promising, showed negative indices for the potential penetration of the Blood Brain Barrier and expressed high human intestinal absorption, indicating a low risk of central nervous system depression or drowsiness as the the side effects. The compound ZINC000006694490 exhibited an alert with a plausible level of toxicity for the purine base chemical moiety, indicating hepatotoxicity and chromosome damage in vivo in mouse, rat and human organisms. All of the compounds selected in this study showed a synthetic accessibility (SA) score lower than 4, suggesting the ease of new syntheses. The results corroborate with other studies in the literature, and the computational approach used here can contribute to the discovery of new and potent anti-dengue agents.

Evaluation of an Ussing Chamber System Equipped with Rat Intestinal Tissues to Predict Intestinal Absorption and Metabolism in Humans.

Oral bioavailability (F) is one of the key factors that need to be determined in drug discovery. This factor is determined by the permeability and solubility of new molecule entities (NMEs) according to the biopharmaceutics classification system (BCS). In the present study, we evaluated the permeability of 22 drugs in rat intestinal tissues using an Ussing chamber system and correlated the permeability with data on human intestinal absorption (Fa) and intestinal availability (Fa×Fg) reported in the literature. The rat intestinal permeability data were better correlated with the combined effect of the absorbed fraction (Fa) and the fraction escaping intestinal metabolism (Fg) than Fa itself. Clear regional dependent absorption was observed for most of the test drugs, and ileal Papp was generally higher than that in other segments. Finally, the function of the efflux transporter P-glycoprotein (P-gp) with regard to oral absorption of substrates was evaluated with an Ussing chamber. We also demonstrated that the rat intestinal stability of the three cytochrome P450 (CYP) substrates was consistent with the human data. An Ussing chamber system incorporating rat intestinal tissue would be a valuable tool to predict human intestinal absorption and metabolism for molecules with various physicochemical properties.

In silico-in vitro estimation of lipophilicity and permeability association for succinimide derivatives using chromatographic anisotropic systems and parallel artificial membrane permeability assay.

Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1-aryl-3-methylsuccinimides and 1-aryl-3-ethyl-3-methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico-calculated lipophilicity and (c) in silico-predicted permeability and absorbability. Non-cellular-based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp . Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2 = 0.614, P < 0.001). Moreover, experimentally determined passive permeability, logPapp , was statistically significantly associated with both in silico-predicted absorption constant, ka (r2 = 0.7886, P < 0.001), and human intestinal absorption (HIA) in percentage (r2 = 0.484, P < 0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non-cellular-based model and in silico-predicted Caco-2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH = 7.4).

1361-P: D-Xylose Test as a Biomarker for Glucose Intestinal Absorption in Humans and Minipigs

Background and Aim: Increasing evidences suggest that intestinal glucose absorption (IGA) plays a distinct role in pathophysiology of type 2 diabetes (T2D) . However, state of the art IGA measurement with multiple tracers techniques are demanding and . We propose D-xylose, a non metabolized pentose, as a proxy to quantify IGA levels to study IGA involvement in T2D. Materials and Methods: First (cross sectional studies) , mixed meal tests including D-xylose (MMT) were performed in 165 patients (lean normoglycemic (NG) ; obese NG, glucose intolerant (IGT) or T2D) and 74 healthy adult minipigs. Second (longitudinal studies) , MMT were performed in minipigs before and after 70% intestinal resection (n = 5) , 70% pancreatectomy (n = 15) , and high fat diet for 2 months (HFD) (n = 4) to quantify D-xylose changes after each intervention. Results: 1h serum D-xylose varied with glucose tolerance status (p&amp;lt;0.005) and was higher in T2D and IGT patients than in obese and lean NG patients In multivariable analysis, 1h postprandial glucose was correlated with D-xylose (r= 0.63; p&amp;lt;0.0001) , independently of insulin secretion (insulinogenic index) and insulin sensitivity (Matsuda index) . In minipigs, D-xylose was also independently correlated with post prandial glucose (r=0.53; p&amp;lt;0.05) . D-xylose appearance was reduced after intestinal resection (p&amp;lt;0.05) , but remained unchanged after pancreatectomy and HFD. Conclusion and Perspectives: Post prandial glucose was independently correlated with D-xylose in humans and minipigs. Interventional studies in minipigs provided direct evidence that D-xylose is associated with IGA, independently of insulin secretion and sensitivity. Disclosure R.Goutchtat: None. F.Pattou: None. C.Marciniak: None. R.Caiazzo: Consultant; Ethicon, Inc., Medtronic. H.Verkindt: None. A.Quenon: None. T.Rabier: None. S.Lapiere: None. V.Raverdy: None. T.Hubert: None. Funding ANR

Chromatographic profile, in silico and in vivo study of the pharmacokinetic and toxicological properties of major constituent present in kefir, the kefiran.

Kefiran is a polysaccharide present in kefir grains that have been widely explored due to its potential health benefits. The objective of this work was to characterize and quantify the components present in the ethanolic extract of milk kefir grains; to study its pharmacokinetic and toxicological properties in silico and evaluate the acute toxicity of the kefiran in zebrafish. The prediction of pharmacokinetic properties was performed by QikProp software. In silico toxicity assessment was performed using the DEREK (deductive estimate of risk from existing knowledge) software. In the chromatographic, kefiran was identified as the major component. Results showed that the kefiran had low human oral absorption and intestinal absorption its due poor solubility profile; low logP value, indicating its lipophilicity and the low MDCK and Caco-2 cells permability, and unable to cross the blood-brain barrier. Kefiran did not present any structural warning for in silico toxicity. In zebrafish, the dose of 2,000mg/kg of kefiran produced nonsignificant alterations in the analyzed organs. It can be said then that kefiran has an acceptable degree of safety for use in the development of drugs or functional foods. Further research such as in vivo testing to confirm its pharmacological potential is currently underway.

The effects of Membrane Lipid Replacement with NTFactor® Lipids on increasing the bioavailability of three test nutrients

Introduction: Previous studies indicated that lipids and nanostructured materials may improve the uptake of nutrients with moderate bioabsorption properties. Objectives: This study evaluated the effects of Membrane Lipid Replacement with NTFactor® Lipids (NTFL) on bioabsorption of three poorly to moderately absorbed nutrients (quercetin, curcumin and coenzyme Q10) utilizing the Caco-2 epithelial cell permeability model. Methods: Transfer across a Caco-2 epithelial cell layer has become a reference standard in the pharmaceutical and nutraceutical industries for in vitro prediction of in vivo human intestinal absorption and bioavailability of orally administered substances. The degree of bioabsorption of the test materials was assessed by monitoring the concentrations of the test materials on each side of the Caco-2 monolayers by liquid chromatography and mass spectroscopy (LCMS/MS analysis).Results: When NTFL was added to each of the three test nutrients, there was increased absorption and transfer across a Caco-2 cell layer in a dose-dependent manner for the three nutrients. When compared individually, CoQ10 with NTFL showed the most significant increase in absorption (2.01-times more compared to controls without NTFL, p=0.0011) at a concentration of NTFL of 10 mg/mL. NTFL also increased absorption and transfer across a Caco-2 cell layer of the other test nutrients, but these results did not achieve the same level of significance. Discussion: A variety of Oral membrane lipid replacement supplements with NTFL, such as various vitamins, minerals and nutrients, have been designed to reduce fatigue, improve health conditions, and protect cellular and especially mitochondrial membranes from damage. Here we used NTFL to demonstrate improvements in absorption and bioavailability of three nutrients. Conclusion: Using the Caco-2 bioabsorption and bioavailability in vitro model we found that NTFL could enhance absorption, bioavailability and uptake of nutrients while providing its own clinically demonstrated health benefits. Keywords: Phospholipids, Membrane Lipid Replacement, CoQ10, curcumin, quercetin, bioavailability, absorption, permeability, Caco2, bio-uptake, bioabsorption, glycerolphospholipids, intestinal absorption

Synthesis, antifungal activity and in silico ADMET studies of benzyl alcohol derivatives

Background and Aims: Fungal infections continue to pose a serious threat to human well-being due to the increasing cases of resistance against the existing antifungal drugs. Consequently, efforts are increasingly focused towards investigating new moieties with potential activity against different fungal species. The object of this work was to synthesize and evaluate the antifungal activity of five benzyl alcohol derivatives against Candida albicans and Trichophyton rubrum and also to study the biochemical as well as the ADMET properties of the compounds in silico. Methods: The target compounds were obtained by the reduction of the appropriate aldehyde using sodium borohydride. Subsequently the compounds were tested against the two fungal species using ketoconazole as the positive control. The biochemical activities as well as the ADMET properties were calculated at DFT/B3LYP/6-311G* basis set with the help of Gaussian09 (G09) software. Results: The findings revealed that some of the compounds exhibited interesting inhibitory action against C. albicans while others against T. rubrum. However, the MIC and MFC results demonstrated that none of the compounds were fungicidal at the concentrations tested. In silico ADMET studies showed that all the compounds have a good cell permeability index, their human intestinal absorption values were within the recommended scale and with good plasma protein binding. Conclusion: The benzyl alcohol derivatives studied in this work have exhibited some encouraging antifungal activity and favorable biochemical as well as pharmacokinetic properties.

Tailoring of new Ni(II), Hg(II) and UO2(II)–hydrazide complexes: characterization, studies in-vitro and in-silico as well as the Hartree-Fock modeling

A new hydrazide ligand was prepared to synthesize Ni(II), Hg(II) and UO2(II) complexes, which elucidated by all possible tools. Accordingly, 1M:2L molar ratio was suggested for Ni(II) and Hg(II) complexes, while UO2(II) complex close to 1:1 ratio. The ligand binds as a bidentate or tridentate mode either as a monobasic via deprotonation of azomethine group or as a neutral with Hg(II) complex. A square-planer geometry was suggested for [Ni(L)2], while the other complexes reveal octahedral geometry. The antimicrobial screening was performed as well as the antioxidant and cytotoxic activity test towards Ehrlich ascites cells. The ligand and its Ni(II) complex produce a notable inhibition for microorganisms, while their antioxidant and cytotoxicity are up to the standards themselves. The DFT/B3LYP and Hartree-Fock (HF) methods were used to optimize the structures under suitable basis sets to obtain essential parameters and 3D-maps. Utilizing Swiss-ADME link reveals the positive response of the ligand to blood brain barrier and human intestinal absorption. Moreover, other silico tests were performed via Pharmacophore and Molecular Operating Environmental module (MOE) against different proteins. Finally, the agreement between vitro and silico results was noticed with the ligand and its Ni(II)complex.

Theoretical activity prediction, structure-based design, molecular docking and pharmacokinetic studies of some maleimides against Leishmania donovani for the treatment of leishmaniasis

BackgroundLeishmaniasis is a neglected tropical disease caused by a group of protozoan of the genus Leishmania and transmitted to humans majorly through the bite of the female sand fly. It is prevalent in the tropical regions of the world especially in Africa and estimated to affect a population of about 12 million people annually. This theoretical study was therefore conducted in support of the search for more effective drug candidates for the treatment of leishmaniasis. This study focuses on the in silico activity prediction of twenty-eight (28) maleimides, structure-based design, molecular docking study and pharmacokinetics analysis of the newly designed maleimides. All the studied compounds were drawn using ChemDraw Ultra and optimized by the density functional theory (DFT) approach using B3LYP with 6-31G⁄ basis set.ResultsThe built QSAR model was found to satisfy the requirement of both internal and external validation tests for an acceptable QSAR model with R2 = 0.801, R2adj = 0.748, Q2cv = 0.710, R2test = 0.892 and cRp2 = 0.664 and has shown excellent prediction of the studied compounds. Among the five (5) protein receptors utilized for the virtual docking screening, pyridoxal kinase (PdxK) receptor (Pdb id = 6k91) showed the strongest binding interactions with compounds 14, 21 and 24 with the highest binding affinities of − 7.7, − 7.7 and − 7.8 kcal/mol, respectively. The selected templates (14, 21 and 24) were used to design twelve (12) new compounds (N1–N12) with higher docking scores than the templates. N7 (affinity = − 8.9 kcal/mol) and N12 (− 8.5 kcal/mol) showed higher binding scores than the reference drug pentamidine (− 8.10 kcal/mol), while N3 and N7–N12 showed higher predicted pIC50 than the templates. Also, the pharmacokinetics properties prediction revealed that the newly designed compounds, obeyed the Lipinski’s rule for oral bio-availability, showed high human intestinal absorption (HIA), low synthetic accessibility score, CNS and BBB permeability and were pharmacologically active.ConclusionsThe activities of the various maleimides were predicted excellently by the built QSAR model. Based on the pharmacokinetics and molecular docking studies therefore, the newly designed compounds are suggested for further practical evaluation and/or validation as potential drug candidates for the treatment of leishmaniasis.

Predicting Impact of Food and Feeding Time on Oral Absorption of Drugs with a Novel Rat Continuous Intestinal Absorption Model.

Intricacies in intestinal physiology, drug properties, and food effects should be incorporated into models to predict complex oral drug absorption. A previously published human continuous intestinal absorption model based on the convection-diffusion equation was modified specifically for the male Sprague-Dawley rat in this report. Species-specific physiologic conditions along intestinal length - experimental velocity and pH under fasted and fed conditions, were measured and incorporated into the intestinal absorption model. Concentration-time (C-t) profiles were measured upon a single intravenous and peroral (PO) dose for three drugs: amlodipine (AML), digoxin (DIG), and glyburide (GLY). Absorption profiles were predicted and compared with experimentally collected data under three feeding conditions: 12-hour fasted rats were provided food at two specific times after oral drug dose (1 hour and 2 hours for AML and GLY; 0.5 hours and 1 hour for DIG), or they were provided food for the entire study. Intravenous versus PO C-t profiles suggested absorption even at later times and informed design of appropriate mathematical input functions based on experimental feeding times. With this model, AML, DIG, and GLY oral C-t profiles for all feeding groups were generally well predicted, with exposure overlap coefficients in the range of 0.80-0.97. Efflux transport for DIG and uptake and efflux transport for GLY were included, modeling uptake transporter inhibition in the presence of food. Results indicate that the continuous intestinal rat model incorporates complex physiologic processes and feeding times relative to drug dose into a simple framework to provide accurate prediction of oral absorption. SIGNIFICANCE STATEMENT: A novel rat continuous intestinal model predicts drug absorption with respect to time and intestinal length. Feeding time relative to dose was modeled as a key effect. Experimental fasted/fed intestinal pH and velocity, efflux and uptake transporter expression along intestinal length, and uptake transporter inhibition in the presence of food were modeled. The model uses the pharmacokinetic profiles of three model drugs and provides a novel framework to study food effects on absorption.