Vepris nobilis plant: a potential source of anticancer agents

Background: Cancer is one of the major causes of death worldwide. Current cancer therapy is costly, it has poor therapeutic outcomes and many side effects. Therefore, new medications are needed. Plants have been used as sources of anticancer drugs. Vepris species have anticancer properties. The purpose of this study is to assess Vepris nobilis, a plant found in Kenya as a potential source of anticancer drugs.Methods: The dichloromethane/methanol (CH2Cl2/MeOH) 1:1 extract of the stem bark of Vepris nobilis led to the isolation of an alkaloid named, 4,6-dimethoxy-7-((3-methylbuta-1,3-dien-1-yl)oxy)furo[2,3-b]quinolone. SwissADME online tool was used to assess the compound’s pharmacokinetic parameters. Pass online tool identified potential targets while protox server described the toxicity of the compound. Chimera and Avogadro softwares were used for molecular docking studies.Results: In-silico pharmacokinetic studies, showed that the isolated compound complied with Lipinski rule of five, it showed high gastrointestinal activity, and it also inhibits cytochrome P450 (CYP) isoforms 1A2, 2C9 and 2C19. In toxicity studies the compound was relatively safe with a predicted median lethal dose (LD50) of 1600 mg/kg, apart from potential immunotoxicity and mutagenicity. Molecular docking studies demonstrated that, the compound has potential anticancer activity, it interacted with deoxyribonucleic acid (DNA) topoisomerase I in an almost similar manner to camptothecin though it had less binding potential.Conclusions: 4,6-dimethoxy-7-((3-methylbuta-1,3-dien-1-yl)oxy) furo[2,3-b]quinolone derived from Vepris nobilis is a potential drug for the management of cancer which can be administered orally.

Molecular Docking Study to Identify Potent Inhibitors of Alpha-synuclein Aggregation of Parkinson’s Disease

Introduction: Parkinson’s disease (PD) is the widespreadneurodegenerative disorder ranked second in this categoriesand PD is also the most common movement disorder. PDdisorder affects more than 0.1% of the total population olderthan 40 years of age. Contemporary, therapies of PD arerestricted to only symptomatic relief without dealing withthe basic disease etiology such as aggregation of αSyn, thusthe progression of the disease continues with the currenttherapies. The major objective of this study was to find outputative inhibitors of human alfa-synuclein to search possibletherapeutics of Parkinson’s disease.Material and Methods: Our study included Moleculardocking study of 3D-Structure of alfa- synuclein of humanretrieved from PDB with their chemical ligands. The proteinligands docking were performed using AutoDock4.2.5.1.Further, Molecular Dynamic Simulation for protein-ligandcomplex of best dock complex was carried out usingGromacs16.10.Result: Total nineteen molecules was selected for dockingstudy out of which Amento flavones molecule shows bestbinding. The molecular docking simulation results indicatethat the protein complexes were stable throughout MDsimulations and thus proteins possess the ability to stability.Conclusion: This study provides an insight of in-silico drugdesigning approach towards alfa- synuclein modulators as apromising therapeutics of Parkinson’s’s disease.

Synthesis, in-vitro antioxidant activity and in-silico prediction of drug-likeness properties of a novel compound: 4-(3,5-Di-tert-butyl- 4-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one

A simple and eco-friendly method has been used for the synthesis of novel compound 4-(3,5-di-tert-butyl-4-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one. The synthesized compound was characterized by its physical andspectral data. This compound was screened for in-vitro antioxidant activity by 1,1-diphenyl-2-picrylhydrazyl (DPPH)and nitric oxide free radical scavenging assays at 100 µM concentration. The DPPH scavenging ability of evaluatedcompound was superior to the synthetic antioxidant butylated hydroxytoluene (BHT) and comparable to the standardascorbic acid. The nitric oxide scavenging ability of the compound was also found greater than the BHT. The insilico prediction of molecular properties and bioactivity scores of synthesized compound and BHT were carried outusing Molinspiration Cheminformatics online software. The study revealed that the predicted compounds obeyedLipinski’s rule of five and showed good intestinal absorption and membrane permeability indicating the drug-likenessproperties of predicted compounds. Finally, the in silico study identified the title compound as a nuclear receptorligand compared to BHT.

Synthesis, in silico study and in vitro anti-microbial evaluation of some new N-benzoyl-N'-[2-(4-chloro-phenoxy)-acetyl]-hydrazides analogs

In bacterial resistance duty, the prompt increase against existent anti-microbial drugs is a challenging universal healthproblem. Bacteria represent a highly significant threat globally to healthcare-associated infections, also responsiblefor the majority of hospital infections, which leads to an increase in the mortality and burden of worldwide healthcareduty. In this investigation, we reported the synthesis novel substitutes of phenoxy hydrazide analogs (6a–f) andhave been screened for in vitro anti-bacterial and anti-fungal activities to determine the inhibition zone by using thepaper disk agar diffusion technique and broth dilution to evaluate the minimum inhibitory concentration values. Thestructure–activity relationship suggest that among the series (6a–f), compounds (6e) with two chloro groups and (6f)with four fluoro groups showed good inhibition against pathogenic microbes. Furthermore, these results were alsoconfirmed by the in silico study. Based on this studies, there are a scopes of developing compounds (6e) and (6f) intopotent anti-microbial drugs in the near future.

Analgesic activity of Alpinia galanga extract in mice models and TNF-alpha receptor computational docking analysis on its leads with pharmacokinetics prediction

Background: Alpinia galanga is an ayurvedic herb recognized and used across many traditional medicine systems for its analgesic and anti-inflammatory activity. The present study scientifically validates the potential anti nociceptive action of ethanolic extract of Alpinia galanga by chemical, neurogenic and inflammatory nociception model in mice followed by identification of potential lead compound by computational analysis.Methods: The assessment of anti nociceptive action is evaluated by Acetic acid induced abdominal constrictions and Formalin assay on ethonolic extract of Alpinia galanga, followed by 20 compounds with known chemical structure of Alpinia galanga is subjected to computational analysis to predict possible lead compound with desirable pharmacokinetic and drug like features.Results: The percentage inhibition rate of Aspirin (100mg/kg) was 82.15% compared to Alpinia galanga (100mg/kg) 19.63%, (200mg/kg) 33.02% and (400mg/kg) 57.13% by acetic acid induced abdominal constrictions antinociceptive mice model. Alpinia galanga 400mg/kg (71.70%) had comparable percentage inhibition of nociception to standard group indomethacin (88.71%) in formalin induced nociceptive mice model. Among 20 compounds screened for pharmacokinetic and drug like features, Galanal B had the binding free energy -56.664 when compared to control compound 2AZ5-56.000.Conclusions: The Alpinia galanga extract had significant anti nociceptive activity and followed by computational analysis of 20 compounds with known chemical structure predicted Galanal B as lead compound with best insilico pharmacokinetic and drug like features.

LC and LC–MS/MS studies for the identification and characterization of degradation products of acebutolol / 药物分析学报

The aim of the present investigation was to demonstrate an approach involving use of liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC–MS) to separate, identify and characterize very small quantities of degradation products (DPs) of acebutolol without their isolation from the reaction mixtures. The drug was subjected to oxidative, hydrolytic, thermal and photolytic stress conditions as per International Conference on Harmonization (ICH) guideline Q1A(R2). Among all the stress conditions the drug was found to be labile in hydrolytic (acidic & basic) and photolytic stress conditions, while it was stable in water-induced hydrolysis, oxidative and thermal stress conditions. A total of four degradation products were formed. A C18 column was employed for the separation of all the DPs on a gradient mode by using high-performance liquid chromatography (HPLC). All the DPs were characterized with the help of their fragmentation pattern and the masses obtained upon LC–MS/MS and MSn analysis. All the hitherto unknown degradation products were identified as 1-(2-(2-hydroxy-3- (isopropylamino)propoxy)-5-(amino)phenyl)ethanone (DP-I), N-(4-(2-hydroxy-3-(isopropylamino) propoxy)-3-acetylphenyl)acrylamide (DP-II), 1-(2-(2-hydroxy-3-(isopropylamino)propoxy)-5-(hydroxymethylamino) phenyl)ethanone (DP-III) and 1-(6-(2-hydroxy-3-(isopropylamino)propoxy)-2,3-dihydro- 2-propylbenzo[d]oxazol-5-yl)ethanone (DP-IV). Finally the in-silico carcinogenicity and hepatotoxicity predictions of the drug and all the DPs were performed by using toxicity prediction softwares viz., TOPKAT, LAZAR and Discovery Studio ADMET. The results of in-silico toxicity studies revealed that acebutolol (0.967) and DP-I (0.986) were found to be carcinogenic, while acebutolol (0.490) and DP-IV (0.437) were found to be hepatotoxic.

A stability-indicating LC–MS/MS method for zidovudine: Identification, characterization and toxicity prediction of two major acid degradation products / 药物分析学报

Zidvovudine (AZT) is a nucleoside analogue reverse transcriptase inhibitor (NRTI), a class of anti-retroviral drug. A stability-indicating assay method for AZT was developed in line with ICH guideline. Successful separation of AZT and its degradation products was achieved by gradient elution mode on reverse phase C18 column using 10 mM ammonium acetate: acetonitrile as the mobile phase at 0.8 mL/min flow rate, 25 μL injection volume, 30 °C column temperature and 285 nm detection wavelength. Two major acid degradation products were identified and characterized by liquid chromatography–electrospray ionization mass spectro-metry (LC–ESI/MS/MS) and accurate mass measurements. The probable mechanisms for the formation of degradation products were identified based on a comparison of the fragmentation pattern of the [M + H] + ions of AZT and its degradation products. One of the degradation products, DP-1, was isolated by semi-preparative high performance liquid chromatography (HPLC) using Waters XBridge Prep C18 (250 mm×10 mm, 5 μm). Degradation products showed higher toxicity compared to the drug in some models assessed by TOPKAT software. The method validation was performed with respect to robustness, specificity, linearity, precision and accuracy as per ICH guideline Q2 (R1).

In silico CRISPR-based sgRNA design / 生物工程学报

CRISPR-based genome editing has been widely implemented in various cell types. In-silico single guide RNA (sgRNA) design is a key step for successful gene editing using CRISPR system. Continuing efforts are made to refine in-silico sgRNA design with high on-target efficacy and reduced off-target effects. In this paper, we summarize the present sgRNA design tools, and show that efficient in-silico models can be built that integrate current heterogeneous genome-editing data to derive unbiased sgRNA design rules and identify key features for improving sgRNA design. Our review shows that systematic comparisons and evaluation of on-target and off-target effects of sgRNA will allow more precise genome editing and gene therapies using the CRISPR system.

Computational drug Cumintrazole-analog for the treatment of mutant BRCA1 and BRCA2 proteins in breast cancer.

Breast cancer is the second death causing disease in the world. Breast cancer gene 1 (BRCA1) and Breast cancer gene 2 (BRCA2) are the controlling proteins of this cancer. Real capacity of BRCA1/BRCA2 is to control the cell division, repair the damaged DNA and stabilized the genetic material of the cell. In case of any mutation in these proteins, the division of breast cells will be modified and therefore the cancerous development of cells will start in breast. The essential target of study was to prepare novel synthetic compound to focus on destinations for receptor proteins, located on cells surface, which control the development or stop the multiplication of cancer cells. Subsequent to screening vast measure of information, we outlined novel in-silico medication compound for breast cancer that is able to hinder the uncontrolled development of cells. In docked edifices PHE and GLN are critical communicating build ups for BRCA1 and BRCA2 proteins. Atomic recipe of shad sample totally fulfills the Lipinski rule of five. It shows less symptoms and long resistance against breast cancer cells. We infer that our medication shad sample is better than the business drugs available in business sector. As it is non-toxic in nature and has no reactions. The proposed drug is suitable for reduction of the breast cancer in females.

ANÁLISIS COMPUTACIONAL DEL EFECTO DE POLIMORFISMOS DE GENES DEL SISTEMA μ-CALPAÍNA/CALPASTATINA SOBRE LA CALIDAD DE LA CARNE BOVINA / COMPUTATIONAL ANALYSIS OF POLYMORPHISMS IN GENES OF THE μ-CALPAIN/CALPASTATIN SYSTEM IN BOVINE MEAT QUALITY

Los genes del sistema de enzimas μ-Calpaína/Calpastatina han sido ampliamente evaluados en estudios de asociación respecto de parámetros de calidad cárnica como la terneza; previamente se han identificado varios polimorfismos asociados con la variación fenotípica en poblaciones no relacionadas de bovinos. Usando herramientas computacionales se logró postular la asociación de cuatro polimorfismos encontrados en μ-Calpaína y 11 en Calpastatina que producen una alteración de los parámetros físico-químicos, tanto del ARNm (estabilidad y polimorfismo conformacional), como de la proteína (punto isoeléctrico, potencial electroestático y superficie molecular). Es importante poder establecer el soporte biológico de polimorfismos genéticos asociados con parámetros fenotípicos que mejoren la productividad animal, lo que hace que la aproximación in silico se convierta en una herramienta útil para tal fin.

μ-Calpain/Calpastatin enzymatic system are extensively evaluated in tenderness association studies of beef quality and several polymorphisms of these same genes have been reported previously associated with phenotypic variation in non-related bovine populations. Computational tools were used to screen four polymorphisms in μ-Calpain gene and 11 in Calpastatin gene that can alter the physical and mRNA chemical properties (stability and conformational polymorphism) and its respective proteins (isoelectric point, electrostatic potential and molecular surface) of polymorphisms previously reported in public databases. In silico aproximation is a useful tool in phenotype-genotype association studies because can provide a biological support to this type of animal production traits.

In-silico designing of NKK: A better ligand than Aciclovir against Herpes Simplex Virus.

Aciclovir is the best dr thymidine kinase made by the HSV. In the current study we have successfully designed a drug candidate “NKK”, which is far more efficient than aciclovir in terms of binding energy and physiochemical properties again used softwares viz. Autodock 4.0, FireDock and Hex dock in order to demonstrate that “NKK” is a better ligand than aciclovir with respect to aforesaid properties.

Computational drug Cumintrazole-analog for the treatment of mutant BRCA1 and BRCA2 proteins in breast cancer

Breast cancer is the second death causing disease in the world. Breast cancer gene 1 (BRCA1) and Breast cancer gene 2 (BRCA2) are the controlling proteins of this cancer. Real capacity of BRCA1/BRCA2 is to control the cell division, repair the damaged DNA and stabilized the genetic material of the cell. In case of any mutation in these proteins, the division of breast cells will be modified and therefore the cancerous development of cells will start in breast. The essential target of study was to prepare novel synthetic compound to focus on destinations for receptor proteins, located on cells surface, which control the development or stop the multiplication of cancer cells. Subsequent to screening vast measure of information, we outlined novel in-silico medication compound for breast cancer that is able to hinder the uncontrolled development of cells. In docked edifices PHE and GLN are critical communicating build ups for BRCA1 and BRCA2 proteins. Atomic recipe of shad sample totally fulfills the Lipinski rule of five. It shows less symptoms and long resistance against breast cancer cells. We infer that our medication shad sample is better than the business drugs available in business sector. As it is non-toxic in nature and has no reactions. The proposed drug is suitable for reduction of the breast cancer in females.

In-silico analysis of heat shock protein 47 for identifying the novel therapeutic agents in the management of oral submucous fibrosis.

Background: Heat shock proteins-47 (HSP47) is a collagen specific molecular chaperone, involved in the processing and/or secretion of procollagen. It seems to be regularly upregulated in various fibrotic or collagen disorders. Hence, this protein can be a potential target for the treatment of various fibrotic diseases including oral submucous fibrosis (OSF), which is a collagen metabolic disorder of oral cavity and whose etiopathogeneic mechanism and therapeutic protocols are still not well documented. Aim: The aim of this study is to identify the novel therapeutic agents using in-silico methods for the management of OSF. Objectives: The objectives of this study are to identify the binding sites of HSP47 on the collagen molecule and to identify the lead compound with anti-HSP47 activity from the library of natural compounds, using in-silico methodology. Materials and Methods: The web-based and tool based in-silico analysis of the HSP47 and collagen molecules are used in this study. The crystal structure of collagen and HSP47 were retrieved from Protein Data Bank website. The binding site identification and the docking studies are done using Molegro Virtual Docker offline tool. Results: Out of the 104 Natural compounds, six ligands are found to possess best binding affinity to the binding amino acid residues. Silymarin binds with the 4AU2A receptor and the energy value are found to be −178.193 with four Hbonds. The other best five natural compounds are hesperidin, ginkgolides, withanolides, resveratrol, and gingerol. Our findings provide the basis for the in-vitro validation of the above specified compounds, which can possibly act as "lead" molecules in designing the drugs for OSF. Conclusion: HSP47 can be a potential candidate to target, in order to control the production of abundance collagen in OSF. Hence, the binding sites of HSP47 with collagen are identified and some natural compounds with a potential to bind with these binding receptors are also recognized. These natural compounds might act as anti-HSP47 lead molecules in designing novel therapeutic agents for OSF, which are so far unavailable.

Clinical Research - Past, Present & Future.

Clinical pharmacology/research has a very interesting history. It started in the 40's of the 20th century through the pioneering work of Harry Gold at Cornell University, New York. Clinical research is an integral part of drug development. Drug development can be hastened by a number of new techniques with reduction in cost. In addition reverse pharmacology approaches for drug discovery have come to occupy a special place. 85% of the neutral antagonists act as inverse agonists. Inverse agonists have a distinct effect on receptor regulation as opposed to neutral antagonists. Orphan receptors constitute about 50% of the GPCRs. It is estimated that now there are nearly 175 orphan receptors after 125 having been deorphanised. Targeting these orphan receptors can lead to about the same number of ligands and antagonists thereof. Polymorphism of cytochrome P450 provides the basis for the use of predictive pharmacogenomics to yield drug therapies that are more efficient and safer. It is estimated that such personalized P450 gene-based treatment would be relevant for 10- 20% of all drug therapy.

Antibacterial, Molecular Docking, DNA Binding and Photocleavage Studies on Novel Heterocyclic Pyrazoles.

The antibacterial activity, in-silico DNA molecular docking, DNA binding and photo cleavage studies of newly synthesized pyrazole is described. Antibacterial potential of these compounds screened against a wide range of Gram-positive and Gram-negative bacteria showed significant zone of inhibition and MIC with standard drug ciproflaxin is investigated. Among all the orientation of binding, fourth orientation showed significant binding and revealed that the binding and docking energy of 4a was -8.62 and -8.66 and inhibition constant 7.46 X e-6. The absorption spectra showed the dynamic interaction with CT DNA and as proficient DNA intercalator (Kb = 4.5×104 M-1). The viscosity measurements and thermal denaturation affords the positive results towards DNA intercalation in both the studies. The light induced DNA damage was pragmatic in the absence of various ‘‘inhibitors’’ shows in photo cleavage activities at 360 nm.