Use of quercetin in animal feed : effects on the P-gp expression and pharmacokinetics of orally administrated enrofloxacin in chicken

Modulation of P-glycoprotein (P-gp, encoded by Mdr1) by xenobiotics plays central role in pharmacokinetics of various drugs. Quercetin has a potential to modulate P-gp in rodents, however, its effects on P-gp modulation in chicken are still unclear. Herein, study reports role of quercetin in modulation of P-gp expression and subsequent effects on the pharmacokinetics of enrofloxacin in broilers. Results show that P-gp expression was increased in a dose-dependent manner following exposure to quercetin in Caco-2 cells and tissues of chicken. Absorption rate constant and apparent permeability coefficient of rhodamine 123 were decreased, reflecting efflux function of P-gp in chicken intestine increased by quercetin. Quercetin altered pharmacokinetic of enrofloxacin by decreasing area under curve, peak concentration, and time to reach peak concentration and by increasing clearance rate. Molecular docking shows quercetin can form favorable interactions with binding pocket of chicken xenobiotic receptor (CXR). Results provide convincing evidence that quercetin induced P-gp expression in tissues by possible interaction with CXR, and consequently reducing bioavailability of orally administered enrofloxacin through restricting its intestinal absorption and liver/kidney clearance in broilers. The results can be further extended to guide reasonable use of quercetin to avoid drug-feed interaction occurred with co-administered enrofloxacin or other similar antimicrobials.Peer reviewedFinal Published versio

Review of QSAR Models and Software Tools for predicting Biokinetic Properties

In the assessment of industrial chemicals, cosmetic ingredients, and active substances in pesticides and biocides, metabolites and degradates are rarely tested for their toxicologcal effects in mammals. In the interests of animal welfare and cost-effectiveness, alternatives to animal testing are needed in the evaluation of these types of chemicals. In this report we review the current status of various types of in silico estimation methods for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their metabolites/degradation products. The review was performed in a broad sense, with emphasis on QSARs and rule-based approaches and their applicability to estimation of oral bioavailability, human intestinal absorption, blood-brain barrier penetration, plasma protein binding, metabolism and. This revealed a vast and rapidly growing literature and a range of software tools. While it is difficult to give firm conclusions on the applicability of such tools, it is clear that many have been developed with pharmaceutical applications in mind, and as such may not be applicable to other types of chemicals (this would require further research investigation). On the other hand, a range of predictive methodologies have been explored and found promising, so there is merit in pursuing their applicability in the assessment of other types of chemicals and products. Many of the software tools are not transparent in terms of their predictive algorithms or underlying datasets. However, the literature identifies a set of commonly used descriptors that have been found useful in ADME prediction, so further research and model development activities could be based on such studies.JRC.DG.I.6-Systems toxicolog

Antibacterial and antibiofilm activities of Prangos acaulis Bornm. extract against Streptococcus mutans: an in silico and in vitro study

Introduction: Streptococcus mutans is a principal pathogenic agent in biofilm formation on the teeth surfaces and subsequently development of dental caries and plaque. Therefore, currently introducing novel anti-bacterial and anti-biofilm agents, especially plant based materials are highly regarded. This study was planned to investigate in silico and in vitro antibacterial activities of Prangos acaulis extracts against S. mutans in single and biofilm forms and their mutagenicity in Ames test. Methods: The anti-bacterial and anti-biofilm effects of methanol extracts from various parts of P. acaulis were evaluated using disk diffusion and microtiter assay. Moreover, the potential mutagenicity of the extracts was investigated using Ames test. In addition, dominant constitutes of P. acaulis that reported in previous studies were subjected to an in silico analysis. The ability of selected phytochemicals to inhibit the glucosyltransferase was evaluated using molecular docking method. Results: All tested extracts especially root extract had significant antibacterial activity against the single form of S. mutans and inhibited biofilm formation without any mutagenic activity. The results also confirmed that three compounds consisting of ar-curcumene, d-limonene and alpha-pinene had strong and appropriate interactions to glucosyltransferase. Conclusion: This study indicated that P. acaulis has potent antibacterial and biofilm inhibition activity against S. mutans and can be good candidate for in vitro and in vivo studies with the aim of introducing novel inhibitors of dental caries developmen

Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs

MEKANISME TEMPE KACANG MERAH (Phaseolus vulgaris L.) SEBAGAI ANTI KOLESTEROL MELALUI PENGHAMBATAN LIPASE PANKREAS DAN Fatty Acids Synthase (FAS) SECARA KOMPUTASI

ABSTRAK  Pendahuluan: Tempe merupakan makanan produk fermentasi yang memiliki kandungan probiotik. Kacang merah memiliki efek antihiperkolesterol dikarenakan dalam kacang merah mengandung proantosianidin dan isoflavon yaitu genestein, daidzein, biochanin A, glycitein, dan formononetin. Tujuan penelitian untuk memprediksi afinitas yang terbentuk antara senyawa aktif tempe kacang merah dengan enzim target serta memprediksi fisikokimia,  ADME, toksisitas senyawa aktif tempe kacang merah.Metode: Penelitian secara in silico dilakukan pada 10 senyawa aktif tempe kacang merah dengan metode molecular docking pada http://www.dockingserver.com. Struktur 3D senyawa aktif  tempe kacang merah dan orlistat diambil dari Pubchem, enzim Lipase pankreas dan Fatty Acid Synthase (FAS)  diambil dari RCSB dan Uniprot. Konversi format pdb menggunakan http://swissmodel.expasy.org. Analisa afinitas senyawa ligan terhadap enzim dengan membandingkan energi bebas, konstanta inhibisi, interaksi permukaan, dan residu asam amino dengan orlistat. Analisa fisikokimia, ADME, dan toksisitas senyawa aktif tempe kacang merah menggunakan pKCSMHasil: Hasil pKSCM online tool didapatkan seluruh senyawa aktif tempe kacang merah memiliki efektifitas yang baik untuk bekerja di intestinal dan tidak mempunyai  efek hepapatotoksik serta efek toksisitas lainnya, sementara catechin diprediksi bersifat karsinogenik. Hasil molecular docking didapatkan Kaempferol-O, Quercetin-O-acylhexoside dan Glisitein memiliki afinitas tinggi dalam menghambat enzim FAS. Genistein mempunyai afinitas rendah dalam menghambat lipase pankreas,namun  diprediksi memiliki potensi yang sama dengan kontrol.Kesimpulan: Seluruh senyawa aktif tempe kacang merah kecuali catechin, efektif bekerja di interstinal dan tidak bersifat toksik. Senyawa aktif tempe kacang merah yang memiliki afinitas terhadap FAS adalah  Kaempferol-O, Quercetin-O-acylhexoside dan Glisitein. Adapun yang memiliki afinitas terhadap lipase pankreas adalah Genistein.Kata Kunci: antikolesterol, tempe, senyawa aktif tempe kacang merah, in silico, pkCSM

In Silico Insight of Natural Compounds in Ageratum Conyzoides L as Anti Breast Cancer Candidate by Molecular Docking Against EGFR

The regulation of proliferation and apoptosis in cancer cells, particularly breast cancer, hinges on the control exerted by the epidermal growth factor receptor (EGFR). Naturally derived EGFR inhibitors from natural compounds show significant potential for future advancements. This study aims to assess the efficacy of active compounds found in Ageratum Conyzoides L as EGFR inhibitors. Evaluation involved molecular docking studies of flavonoid, chromene, terpene, sterol, and acid compounds against EGFR using PDB ID 1m17. Additionally, the ADMET properties and drug-like characteristics of the most promising compounds were characterized. Findings reveal that compound C2 (fisetin) exhibits the most favorable binding energy of -8.9 kcal/mol. Fisetin establishes crucial interactions, particularly with the catalytic site at Met765 of the hinge protein. Fisetin also engages in hydrophobic interactions in regions I and II, involving Val702, Leu694, and Leu820. ADMET profiling of fisetin demonstrates favorable attributes, suggesting its potential as a promising anticancer agent based on drug-likeness assessments

DOCKING MOLEKULER SENYAWA POTENSIAL DAUN KELOR (Moringa oleifera) TERHADAP RESEPTOR FOLAT

Asam folat merupakan mikronutrien yang sangat diperlukan oleh ibu hamil dalam perkembangan sistem saraf. Konsumsi daun kelor dapat meningkatkan kadar hemoglobin yaitu >11 gr%. Potensi zat gizi yang terkandung dalam daun kelor mampu memenuhi kebutuhan zat gizi ibu hamil. Namun identifikasi senyawa aktif tersebut terhadap makromolekul atau target aksi molekuler asam folat belum diketahui dengan jelas. Penelitian ini bertujuan untuk mengidentifikasi kandungan kimia daun kelor yang dapat berinteraksi dengan reseptor folat secara in silico serta prediksi parameter farmakokinetika basis webserver SwissADME. Target molekuler yang dipilih adalah reseptor folat alfa (PDB: 4LRH) dengan teknik docking molekuler menggunakan Autodock 4.2 yang telah dilakukan validasi sebelumnya terhadap ligan asli. Target molekuler yang dipilih adalah reseptor folat alfa (PDB: 4LRH) dengan teknik docking molekuler menggunakan Autodock 4.2 yang telah dilakukan validasi sebelumnya terhadap ligan asli. Hasil docking molekuler menunjukkan bahwa senyawa potensial daun kelor adalah glucosinalbin, niazidin, niazinin, niazirin dan rhamnetin yang memiliki nilai energi ikatan kurang dari -8 kkal/mol. Namun senyawa potensial tersebut tidak lebih kurang dari nilai energi ikatan asam folat sebagai ligan asli pada makromolekul reseptor asam folat alfa. Hasil prediksi parameter farmakokinetika menunjukkan bahwa seluruh senyawa potensial daun kelor menunjukkan bahwa niazinin, niazirin dan rhamnetin terabsorpsi dengan tinggi dalam saluran gastrointestinal, kecuali niazidin dan glucosinalbin. Rhamnetin merupakan senyawa potensial yang dapat dikatalisis oleh enzim CYP3A4, CYP1A2 dan CYP2D6

Mengungkap Aktivitas Antikanker Senyawa Dihidrokaempferida secara In Silico

This study aims to perform molecular docking of dihydrokaempferide and to predict the ADMET profiles of dihydrokaempferide. The molecular docking was conducted on DAPK1 macromolecules (5AUX and 5AV3) by preparation of dihydrokaempferide, preparation of DAPK1, docking simulation of dihydrokaempferide, visualization of docking results, and ADMET analysis. The molecular docking of dihydrokaempferide produced a binding affinity value of -6.9 kcal/mol for 5AUX and of -5.7 kcal/mol for 5AV3. The ADMET prediction indicated dihydrokaempferide had good physicochemical properties according to the criteria of absorption, distribution, metabolism, excretion, and toxicity

Uji Potensi Senyawa Metabolit Sekunder Tanaman Putri Malu (Mimosa pudica L.) Sebagai Inhibitor Xanthine Oxidase Secara In Silico

ABSTRAKXantin oksidase merupakan enzim yang berperan sebagai katalisator dalam oksidasi hipoksantin menjadi xantin dan xantin menjadi asam urat. Peningkatan kadar asam urat disebut dengan hiperurisemia yaitu kondisi kadar asam urat serum meningkat melebihi dari nilai normal yaitu >6 mg/dL pada wanita dan >7 mg/dL pada pria yang mana dapat menyebabkan komplikasi seperti pirai dan batu ginjal. Secara in vivo dan in vitro, putri malu (Mimosa pudica L.) memiliki aktivitas sebagai inhibitor xantin oksidase. Penelitian ini dilakukan dengann tujuan untuk mengetahui senyawa metabolit sekunder  herba putri malu yang berpotensi dalam menghambat aktivitas enzim xantin oksidase. Penelitian ini dilakukan dengann metode in silico molecular docking yaitu penambatan ligan uji dari 14 senyawa metabolit sekunder herba putri malu dengan xantin oksidase (PDB ID: 3NVW) menggunakan program Autodock 4.2 dengan senyawa pembanding Allopurinol. Hasil yang diperoleh menunjukkan senyawa uji terbaik yang berpotensi menghambat aktivitas xantin oksidase yang ditandai dengan rendahnya nilai energi bebas (-∆G) yaitu hernancorizin (-10,12 kcal/mol), crocetin (-8,53 kcal/mol),  luteolin (-8,48 kcal/mol), diplotasin (-8,35kcal/mol), quersetin (-8,20 kcal/mol), dan mimopudin (-8,05 kcal/mol). Selain itu, asam amino yang paling banyak terlibat berdasarkan hasil interaksi pembentukan ikatan hidrogen ligan-protein yaitu Glu 802, Arg 880, Glu 1261 dan Thr 1010. Berdasarkan hasil penambatan yang dilakukan, senyawa hernancorizin memiliki potensi besar dalam penghambatan enzim xantin oksidase karena memiliki kekuatan dan kestabilan yang tinggi dengan energi penambatan terendah ketika ditambatkan dengan protein target. Kata kunci :Autodock 4;Hiperurisemia;Inhibitor xantine oksidase;Mimosa pudica L;Penambatan molekul.ASBTRACTXanthine oxidase is an enzyme that acts as a catalyst in the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Increased uric acid levels are called hyperuricemia, which is a condition where serum uric acid levels increase beyond the normal value, namely > 7 mg/dL in men and > 6 mg/dL in women, which can cause complications such as gout and kidney stones. In vitro and in vivo, Putri malu (Mimosa pudica L.) can inhibit xanthine oxidase activity. This study was conducted to determine the content of secondary metabolites in the Putri malu herb, which is thought to determine the activity of the xanthine oxidase enzyme. This research was carried out in silico with ligand tethering of 14 secondary metabolites of the Putri malu herb with xanthine oxidase (PDB ID: 3NVW) using the Autodock 4.2 program with the comparison compound Allopurinol. The results showed that the best compounds that might inhibit xanthine oxidase activity were characterized by a low value of free energy (-∆G) namely hernancorizin (-10,12 kcal/mol), crocetin (-8,53 kcal/mol),  luteolin (-8,48 kcal/mol), diplotasin (-8,35kcal/mol), quercetin (-8,20 kcal/mol), dan mimopudine (-8,05 kcal/mol). Selain In addition, the most involved amino acids based on the interaction of hydrogen ligand-protein interactions were Glu 802, Arg 880, Glu 1261 and Thr 1010. Based on the tethering results, hernancorizin has great potential in inhibiting xanthine oxidase because it has high strength and stability with the lowest binding energy when attached to the target protein. Keywords : Autodock 4; Hyperuricemia; Xanthine Oxydase; Mimosa pudica L; Molecular docking