Blind docking of 4-Amino-7-Chloroquinoline analogs as potential dengue virus protease inhibitor using CB Dock a web server-Supplemenntary data

Currently, there is no approved drug to combat dengue. Various quinoline derivatives are known for potential antimalarial, antiviral activities, etc. In the present work docking between 4-Amino-7-Chloroquinoline analogs was performed with dengue virus NS2B/NS3 protease using CB dock, a web server. Lys74, Ile165, Val147, Asn152, Asn167, Trp83 and Leu149 amino acid residues were found to be in contact with designed 4-Amino-7-Chloroquinoline analogs. Different modes of binding like hydrogen bonding, hydrophobic interactions, etc with designed compounds improve potential anti-dengue characteristics in silico. ADME results are in acceptable range.

Blind docking of 4-Amino-7-Chloroquinoline analogs as potential dengue virus protease inhibitor using CB Dock a web server

Currently, there is no approved drug to combat dengue. Various quinoline derivatives are known for potential antimalarial, antiviral activities, etc. In the present work docking between 4-Amino-7-Chloroquinoline analogs was performed with dengue virus NS2B/NS3 protease using CB dock, a web server. Lys74, Ile165, Val147, Asn152, Asn167, Trp83 and Leu149 amino acid residues were found to be in contact with designed 4-Amino-7-Chloroquinoline analogs. Different modes of binding like hydrogen bonding, hydrophobic interactions, etc with designed compounds improve potential anti-dengue characteristics in silico. ADME results are in acceptable range.

Design, synthesis, in silico studies, and antidiabetic activity of several sulfanilamide incorporated 2,3-disubstitut-ed thiazolidin-4-ones

A panel of 2,3-disubstituted thiazolidin-4-ones 4a-n was synthesised from Schiff bases 3a-n derived from sulfanilamide, by reaction with thioglycolic acid. The compounds were characterised by means of IR, NMR, and Mass spectral data. Compounds 4a-n were screened for DPPH scavenging assay and compounds 4e, 4h, 4i, and 4n exhibited moderate activity. Compounds 4e, 4h, and 4i were tested at 200 mg/kg and 4e at 50 mg/kg b.w. orally for antidiabetic activity in fructose induced diabetic rats. They exhibited significant antidiabetic activity compared to the control group. Pioglitazone was used as a standard drug. The tested compounds exhibited better and ignificant serum cholesterol lowering activity when compared with the control and standard groups. They also reduced the triglyceride level after the 21st day; however, it was insignificant when compared to the control group. Compound 4n displayed the highest binding energy when docked with PPAR-γ followed by compounds 4e, 4h, and 4i when compared to pioglitazone. The physicochemical, drug likeness and ADME properties of the title compounds were found to be satisfactory.

Se sintetizó un panel de tiazolidinas-4-onas 2,3-disustituidas 4a-n a partir de las bases de Schiff 3a-n derivadas de la sulfanilamida por reacción con ácido tioglicólico. Los compuestos se caracterizaron por IR, RMN y datos espectrales de masa. Los compuestos 4a-n se analizaron para DPPH y los compuestos 4e, 4h, 4i y 4n mostraron una actividad moderada. Los compuestos 4e, 4h y 4i se probaron a 200 mg/kg y 4e a 50 mg/kg b.w. oralmente para la actividad antidiabética en ratas diabéticas, inducida por fructosa. Los compuestos mostraron una actividad antidiabética muy significativa en comparación con el grupo control. La pioglitazona se utilizó como fármaco estándar. Los compuestos ensayados mostraron una mejor y significativa actividad reductora del colesterol sérico en comparación con los grupos control y estándar. Estos compuestos también redujeron el nivel de triglicéridos después del 21° día, aunque fue insignificante en comparación con el grupo control. El compuesto 4n mostró la mayor afinidad de unión cuando se acopló a PPAR-γ, seguido de 4e, 4h y 4i en comparación con la pioglitazona. Las propiedades fisicoquímicas, la similitud con el fármaco y las propiedades ADME de los compuestos fueron satisfactorias, lo que los convierte en útiles agentes antidiabéticos.

Um painel de 2,3-disubstituído thiazolidina-4-ones 4a-n foram sintetizados a partir de bases Schiff 3a-n derivado da sulfanilamida por reacção com ácido tioglicólico. Os compostos eram caracterizado por IR, NMR e dados espectrais de massa. Os compostos 4a-n foram rastreados para O ensaio DPPH de limpeza radical e os compostos 4e, 4h, 4i e 4n exibiram actividade moderada. Os compostos 4e, 4h e 4i foram testados a 200 mg/kg e 4e a 50 mg/kg de peso corporal por via oral para antidiabéticos. actividade em ratos diabéticos induzidos por frutose. Exibiram uma actividade antidiabética altamente significativa actividade em comparação com o controlo. A pioglitazona foi utilizada como droga padrão. Os compostos testados exibiu uma melhor e significativa actividade de redução do colesterol sérico quando comparado comde triglicéridos após o 21° dia; no entanto, foi insignificante quando comparado com o controlo. O composto 4n mostrou a maior afinidade de ligação quando acoplado com PPAR-γ seguido de 4e, 4h, 4i quando comparado com pioglitazona. O propriedades físico-químicas, de semelhança com drogas e ADME dos compostos do título de propriedade também foram encontrados paraser satisfatórios, tornando-os agentes antidiabéticos úteis.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Preclinical efficacy against acute myeloid leukaemia of SH1573, a novel mutant IDH2 inhibitor approved for clinical trials in China

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, with increasing incidence with age and a generally poor prognosis. Almost 20% of AML patients express mutant isocitrate dehydrogenase 2 (mIDH2), which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate (2-HG), resulting in poor prognosis. Thus, global institutions have been working to develop mIDH2 inhibitors. SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised. We have conducted a comprehensive study on its pharmacodynamics, pharmacokinetics and safety. First, SH1573 exhibited a strong selective inhibition of mIDH2 R140Q protein, which could effectively reduce the production of 2-HG in cell lines, serum and tumors of an animal model. It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models. Then, it was confirmed that SH1573 possessed characteristics of high bioavailability, good metabolic stability and wide tissue distribution. Finally, toxicological data showed that SH1573 had no effects on the respiratory system, cardiovascular system and nervous system, and was genetically safe. This research successfully promoted the approval of SH1573 for clinical trials (CTR20200247). All experiments demonstrated that, as a potential drug against mIDH2 R140Q acute myeloid leukaemia, SH1573 was effective and safe.

Evaluación in silico del efecto de compuestos fenólicos de Pleurotus ostreatus sobre la enzima 5-lipoxigenasa (5- LOX) / In silico evaluation of the effect of Pleurotus ostreatus phenolic compounds on the enzyme 5-lipoxygenase (5-LOX)

Introducción: Los hongos comestibles, en particular Pleurotus ostreatus, representan una importante fuente de metabolitos bioactivos con propiedades inmunomoduladoras, antioxidantes y antiinflamatorias. Trabajos recientes han demostrado que extractos y compuestos purificados a partir de esta seta, entre ellos, la fracción rica en fenoles, inhiben el factor nuclear kappa B(NF-κB), la cicloxigenasa (COX) y modulan cascadas de señalización relacionadas con el balance redox. De acuerdo con estos antecedentes, dichos compuestos podrían actuar, además, como inhibidores de la enzima 5- lipoxigenasa (5-LOX). Objetivo: Evaluar el efecto in silico de trece compuestos fenólicos presentes en la especie Pleurotus ostreatus sobre la enzima 5-LOX, al utilizar como compuesto de referencia la mangiferina. Métodos: El acoplamiento se llevó a cabo a través del programa AutoDock 4.2 (http://autodock.scripps.edu) y la estructura de 5 LOX se obtuvo con la base de datos de proteínas, PDB (www.wwpdb.org). Se estimaron la energía libre (ΔG), la constante de disociación (Ki) y la eficiencia de ligando (LE). Se obtuvieron los parámetros de similitud a un fármaco y los relacionados con la absorción, distribución, metabolismo, excreción y toxicidad (ADME/T) de los mejores modelos de acoplamiento. Resultados: Los mejores indicadores de ΔG y Ki, correspondieron a los ácidos homogentísico, clorogénico y gentísico, con valores de ΔG (-11,81; -12,28 y -11,67 kcal/moL) y Ki (2,19 10-9; 9,99 10-10, 2,79 10-9 M), respectivamente. La eficiencia de ligando alcanzó valores adecuados para estos tres compuestos fenólicos. El modelo de acoplamiento del ácido homogentísico mostró los mejores resultados en cuanto a la similitud a un fármaco y pruebas ADME/T. Conclusiones: El estudio in silico reveló las potencialidades de la fracción rica en fenoles de P. ostreatus, y en particular, del ácido homogentísico como inhibidor de la enzima 5 -LOX, y justifica el desarrollo de ensayos confirmativos in vitro/ in vivo que corroboren sus efectos antioxidantes y antinflamatorios(AU)

Introduction: Edible mushrooms, Pleurotus ostreatus in particular, are an important source of bioactive metabolites with immunomodulatory, antioxidant and anti-inflammatory properties. Recent studies have shown that extracts and compounds purified from this mushroom, among them the phenol-rich fraction, inhibit nuclear factor kappa B (NF-κB), cyclooxygenase (COX), and modulate signaling cascades related to redox balance. According to these antecedents, such compounds could also act as inhibitors of the enzyme 5-lipoxygenase (5-LOX). Objective: Evaluate the in silico effect of 13 phenolic compounds present in the species Pleurotus ostreatus on the enzyme 5-LOX using mangiferin as reference compound. Methods: Docking was carried out with the software AutoDock 4.2 (http://autodock.scripps.edu) and the 5-LOX structure was obtained with the protein database PDB (www.wwpdb.org). Estimation was performed of free energy (ΔG), dissociation constant (Kd) and ligand efficiency (LE). Drug-likeness parameters were obtained, as well as those related to absorption, distribution, metabolism, excretion and toxicity (ADMET) of the best docking models. Results: The best ΔG and Kd indicators were homogentisic, chlorogenic and gentisic acids, with ΔG and Kd values of -11.81, -12.28, -11.67 kcal/mol, and 2.19 10-9, 9.99 10-10, 2.79 10-9 M, respectively. Ligand efficiency achieved adequate values for these three phenolic compounds. The docking model for homogentisic acid showed the best results in terms of drug likeness and ADMET tests. Conclusions: The in silico study revealed the potential of the phenol-rich fraction of P. ostreatus, homogentisic acid in particular, as an enzyme 5-LOX inhibitor, and justifies the development of confirmatory in vitro / in vivo assays to corroborate its antioxidant and anti-inflammatory effects(AU)

Investigating Drug Properties Of Bioactive Compounds Of Cymbopogon Citratus By Absorption, Distribution, Metabolism, Excretion/Toxicity And Molecular Docking Analysis Against Apolipoprotein N-Acyl Transferase

Delivering a potential drug is a predominant challenge in medicinal chemistry.in this study, bio organic compounds of Cymbopogon citratus was screened by analysing physiochemical properties like solubility, permeability, efficacy, toxicity, and metabolic stability. The optimization of drug potential against virulent protein was calculated by using docking algorithm Autodock 4.2.3. Structure based ligand docking reveals that the compounds having better inhibition potential against virulent enzymes with insoluble and impermeable activities. The organic compounds of Cymbopogon citratus were screened using Lipinski rule of five and ADME/T prediction for drug likeliness. The structure based ligand docking was done between bioactive compounds of plant and virulent protein that cause diseases. The interaction was visualized using Discovery studio and was studies. The molecular docking of bioactive compounds resulted in better inhibition potential with controlled lipophilicity level, without causing toxicity that harms the natural habitat of humans. The compounds, 1,3,4-trimethyl -3cyclohexene-1-carboxaldehyde exhibit binding energy -4.70 Kcal/mol followed by β-myrcene – 4.35 Kcal/mol and Geraniol -4.35 Kcal/mol. Hence, structure based ligand docking and in silico ADME/T studies revealed that the compounds have better inhibition potential against Apolipoprotein by improving the prediction of drug compounds.

Current status and future directions of high-throughput ADME screening in drug discovery / 药物分析学报

During the last decade high-throughput in vitro absorption, distribution, metabolism and excretion (HT-ADME) screening has become an essential part of any drug discovery effort of synthetic molecules. The conduct of HT-ADME screening has been"industrialized"due to the extensive development of software and automation tools in cell culture, assay incubation, sample analysis and data analysis. The HT-ADME assay portfolio continues to expand in emerging areas such as drug-transporter interactions, early soft spot identification, and ADME screening of peptide drug candidates. Additionally, thanks to the very large and high-quality HT-ADME data sets available in many biopharma companies, in silico prediction of ADME properties using machine learning has also gained much momentum in recent years. In this re-view, we discuss the current state-of-the-art practices in HT-ADME screening including assay portfolio, assay automation, sample analysis, data processing, and prediction model building. In addition, we also offer perspectives in future development of this exciting field.

In silico molecular docking and ADME/T analysis of plant compounds against IL17A and IL18 targets in gouty arthritis

Accumulation of urate crystals and subsequent inflammation are the major cause of pathogenesis of gout. Twopro inflammatory cytokines IL17A and IL18 are upregulated in the serum of gout patients and plays a major rolein promoting inflammation. Inhibition of these cytokines by plant phytochemicals would reduce the severity ofinflammation in gout. In the present study, in silico analysis of inhibition of IL17A and IL18 by 10 plant phytochemicalswere studied using the AutoDock 4.2 based on the principles of Lamarckian genetic algorithm. The results revealed abinding energy in the range of −6.32 kcal/mol to −3.5 kcal/mol and interacted with the amino acids in active pocketof IL17A and IL18. Among all the compounds, syringaresinol showing the least binding energy of −6.05 kcal/molwith IL17A and −6.32 kcal/mol with IL18. The control drug, allopurinol showed a binding energy of −3.32 and −3.18kcal/mol with IL17A and IL18, respectively. In addition, ADME/T properties of the compounds were also analyzed topredict their drug likeliness. This docking study can be used for developing potent inhibitors of IL17A and IL18 forthe treatment of gout.

Pharmacokinetic characteristics of 14CCHMFL-FLT3-122 in rats / 药学学报

The study was conducted to characterize the pharmacokinetics, distribution, metabolism and excretion of CHMFL-FLT3-122 after a single oral dose of 50 mg·kg-1 [14C] labeled CHMFL-FLT3-122 in rats. Isotope tracing techniques were used to analyze drug concentration and identify the distribution of drugs in tissues and metabolites in biological samples. The experiments were approved by the Animal Ethics Committee of XenoBiotic Laboratories-China, Inc. The absolute bioavailability in male and female rats were 45.83% and 50.92% respectively. The parent drug and its metabolites were extensively distributed in the stomach, intestine, liver and lung, and were eliminated completely in 48 h. The majority of radioactivity was excreted through the feces at 92.34% of the dose with a small fraction through urine at 3.99% of the dose. The parent drug was the most significant circulating component, representing 49.23% and 70.65% over the 0-48 h collection time interval in the plasma of male and female. Two major metabolites, M553 (sulfate conjugate) and M457 (N-dealkyl product), were identified in plasma. Metabolites of CHMFL-FLT3-122, including ten phase I and four phase II metabolites, were identified. The metabolic pathways of CHMFL-FLT3-122 were proposed as N-dealkylation, oxidation, amide hydrolysis, sulfate conjugation, and glucuronic conjugation.

Pharmacodynamic effect and virulent effect of Tripterygium wilfordii based on network pharmacology / 中国中药杂志

To investigate the pharmacodynamic effect and virulent effect of the main components of the toxic Chinese medicine Tripterygium wilfordii,such as triptolide,tripchlorolide,tripterine,demethylzeylasteral,wilfotrine and euonine,the admet SAR online assessment system was used to calculate the properties of the main components of T. wilfordii. The potential targets of the components were mined and collected through multiple databases,and the potential targets were enriched by the bioinformatics database DAVID.Cytoscape software was used to establish a " target-pathway" network and perform topology analysis on the network. The main chemical components of T. wilfordii were able to penetrate the blood-brain barrier and had intestinal permeability. A total of 65 targets were predicted,including pathways in cancer,hepatitis B,rheumatoid arthritis,and chagas disease( American trypanosomiasis),Toll-like receptor signaling pathway,apoptosis,colorectal cancer,NF-kappa B signaling pathway,etc. T. wilfordii mainly plays a role in the treatment of immune diseases and cancer by regulating inflammatory signaling pathways and cancer signaling pathways. Its action on apoptosis pathway and drug metabolism enzymes may be the mechanism of its toxicity.

Bioengineered miR-27b-3p and miR-328-3p modulate drug metabolism and disposition the regulation of target ADME gene expression

Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion (ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression imperfect complementary Watson-Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette sub-family G member 2 (ABCG2) are regulated by miR-27b-3p and miR-328-3p, respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down and mRNA and their protein levels, respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 1'-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise, BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.

Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications

Advancements in techniques of lead molecule selection have resulted in the failure of around 70% of new chemical entities (NCEs). Some of these molecules are getting rejected at final developmental stage resulting in wastage of money and resources. Unfavourable physicochemical properties affect ADME profile of any efficacious and potent molecule, which may ultimately lead to killing of NCE at final stage. Numerous techniques are being explored including nanocrystals for solubility enhancement purposes. Nanocrystals are the most successful and the ones which had a shorter gap between invention and subsequent commercialization of the first marketed product. Several nanocrystal-based products are commercially available and there is a paradigm shift in using approach from simply being solubility enhancement technique to more novel and specific applications. Some other aspects in relation to parenteral nanosuspensions are concentrations of surfactant to be used, scalability and fate. At present, there exists a wide gap due to poor understanding of these critical factors, which we have tried to address in this review. This review will focus on parenteral nanosuspensions, covering varied aspects especially stabilizers used, GRAS (Generally Recognized as Safe) status of stabilizers, scalability challenges, issues of physical and chemical stability, solidification techniques to combat stability problems and fate.

Research development of ginkgo terpene lactones / 中国中药杂志

Ginkgo terpene lactones, as an important active ingredient from Ginkgo leaves, has high medicinal values and has been widely used in clinics. This article would review the researches both at home and abroad, including chemical composition, structure-activity relationship, analytical methods, pharmacological effects, pharmacokinetic characteristics, and so on, providing a reference for further development and utilization of ginkgo terpene lactones.

Molecular docking, synthesis and in vitro antimalarial evaluation of certain novel curcumin analogues

ABSTRACT The receptor protein PfATP6 has been identified as the common target of artemisinin and curcumin. The work was initiated to assess the antimalarial activity of six curcumin derivatives based on their binding affinities and correlating the in silico docking outcome with in vitro antimalarial screening results. A ligand library of thirty two Knoevenagel condensates of curcumin were designed and docked against PfATP6 protein and six compounds with the best binding scores were synthesized and screened for their antimalarial activity against the sensitive 3D7 strain of Plasmodium falciparum. ADME/Tox, pharmacokinetic and pharmacodynamic profiles of the designed compounds were analyzed and reported. 4-FB was found to have similar binding energy to the standard artemisinin (-6.75 and -6.73 respectively) while 4-MB, 3-HB, 2-HB, B, 4-NB displayed better binding energy than curcumin (-5.95, -5.89, -5.68, -5.35, -5.29 and -5.25 respectively). At a dose of 50 µg/mL all the six compounds showed 100% schizont inhibition while at 5µg/ml, five showed more than 75% inhibition and better results than curcumin. 4-FB showed the best activity with 97.8% schizonticidal activity. The in vitro results superimpose the results obtained from the in silico study thereby encouraging development of promising curcumin leads in the battle against malaria.

A Progress on ADME and the Toxicity of Fructus Psoralea / 世界科学技术-中医药现代化

Fructus psoralea is a tonic traditional Chinese herb commonly used in clinic.The chemical constituents of Fructus psoralea are complicated,mainly containing coumarins,flavonoids and monoterpene phenols with various pharmacological effects.Since the increasing number of reports on the toxicity of Fructus psoralea in clinic,the side effects including toxicity on the liver and kidney,as well as skin allergies have gradually attracted attention.The toxicity of Fructus psoralea is produced from ADME (absorption,distribution,metabolism and excretion) in vivo.In this paper,we collected and clarified the studies of ADME of Fructus psoralea in vivo,and summarized recent adverse clinical events and research over its toxicity.We propose to make a thorough study on the toxic material basis of Fructus psoralea and the toxicological mechanism of its extraction,fractions and compounds.The review provided a possible reference and the direction of research for the safe clinical use of Fructus psoralea.

ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.

Identification of novel PPARγ agonist from GC-MS analysis of ethanolic extract of Cayratia trifolia (L.): a computational molecular simulation studies.

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a nuclear receptor family transcription factor that is expressed in several types of cancers. Antiproliferative and proapoptotic actions of PPARγ agonists suggesting that, it could be a promising therapeutic target for the treatment of variety of cancers. Therefore, the main aim of this study is attempt to identify the novel PPARγ agonist from presence of bioactive compounds in ethanolic extract of Cayratia trifolia using GC-MS analysis and Computational molecular simulation studies. The GC-MS analysis revealed that the ethanolic extract of Cayratia trifolia (L.) (whole plant) consist of 20 bioactive compounds which embrace many biological activities against variety of diseases. Molecular docking studies (Glide 5.5 from Schrödinger suite) exposed that, out of 20 bioactive compounds, Cyclopentadecane, 9- Borabicyclo [3.3.1]nonane, 9-(2-propen-1-yloxy)-.1, 4,8,12,16-Tetramethylheptadecan-4- olide, Oxirane and Vitamin E shows the better glide score. ADME properties (QikProp 2.3 from Schrödinger suite) of these bioactive compounds were under the acceptable range. Based on the result it can be concluded that, these bioactive compounds may act as a good agonist for PPARγ. In future it may focus on current discoveries in PPARγ activation and possible anticancer therapeutic option.

Binding affinity of asiatic acid derivatives design against Inducible Nitric Oxide Synthase and ADMET Prediction.

Asiatic acid (AA) is a pentacyclic triterpenoid compound isolated from pegagan (Centella asiatica) and is reported to show anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS), an isoenzyme responsible for the catalysis of nitric oxide formation. The aim of this study was to obtain information regarding binding affinity of some potential asiatic acid derivatives to iNOS as well as pharmacokinetic properties including oral absorption, distribution, metabolism, and toxicity (ADME/T) using in silico methods. Twelve AA derivatives that were produced by modeling of AA on A- or C-ring or its carboxylic acid group, were included in this study. The affinities of these compounds were studied using molecular docking methods, while pharmacokinetic properties were studied using the PreADMET online program. The results showed that eight AA derivative designs have lower free energy binding (FEB) in comparison to AA (–9.79 kcal/mol), while four of the compound designs showed higher FEB than AA. 2,3-dioxo-11,13 diene-23-carboxy asiatic acid (7) showed the lowest FEB of -11.33 kcal/mol. This compound has the human intestinal absorption (HIA), Caco-2 cell permeability, and plasma protein binding values of 96.62%, 20.90 (nm/Sec.), and 98.46%, respectively, which are comparable to those of AA and other AA derivatives. It is concluded that 2,3-dioxo-11,13 diene-23-carboxy asiatic acid (7) is an AA derivative with potential to be developed as a potential iNOS inhibitor.

Pharmacokinetic aspects and in vitro-in vivo correlation potential for lipid-based formulations

Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.