Helix-Coil Transition Signatures B-Raf V600E Mutation and Virtual Screening for Inhibitors Directed Against Mutant B-Raf.


BACKGROUND:Mutation in the B RAF at V600E has been well implicated in the carcinogenesis that makes it as an attractive therapeutictarget. In the present study, we sought to identify the basis of V600E mutation at functional and structural grounds. The study also endeavors in identification of small molecule as a potential candidate with considerable pharmacological profile than available BRAF inhibitors through computational approaches. METHODS:The functional effects of V600E mutation was predicted using SIFT and Polyphen servers. Protein structural alterations werepredicted using SDM server and RMSD calculations. Virtual screening was performed considering existing BRAF inhibitors viz., Vemurafenib, Sorafenib, Dabrfenib, Trametinibthat formed query compounds for shape similarity search by Tanimoto similarity indices with a threshold of 95%. Compound with high affinity as similar to query compound was retrieved and screened for its ADMET properties. RESULTS:The SNP was shown to be highly vulnerable to malfunction and have damaging effects. Mutated protein showed that the secondary structure was irregular and side chain hydrogen bonds were unsaturated. The superimposition of wild onto mutated V600E BRAF revealed helix-coil transition occurring wherein residues Val 502, Leu 505, Arg506, Lys 507 assumed coiled conformation in the mutated BRAF. Virtual screening led to identification of SCHEMBL298689 akin to Vemurafenib as high affinity B-Raf inhibitors; with least toxicity and optimal bioactivity. CONCLUSION:In the present investigation, we put forth the structural and functional basis of B RAF V600E mutation showing helix coil transitions. In addition identified high affinity compound targeting V600E B RAF through virtual screening.


Curr Drug Metab


Current drug metabolism


Bandaru S,Sumithnath TG,Sharda S,Lakhotia S,Sharma A,Jain A,Hussain T,Nayarisseri A,Singh SK




Has Abstract


2017-07-21 00:00:00














  • Ocular disposition, pharmacokinetics, efficacy and safety of nanoparticle-formulated ophthalmic drugs.

    abstract::Ophthalmic drugs are delivered to ocular tissues predominantly via relatively simple formulations, such as topically dosed water-soluble drug solutions and water-insoluble drug suspensions in ointments. An ideal topical drug delivery system should possess certain desirable properties, such as good corneal and conjunct...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Bu HZ,Gukasyan HJ,Goulet L,Lou XJ,Xiang C,Koudriakova T

    更新日期:2007-02-01 00:00:00

  • Review of and perspectives on the toxicology of graphene-based materials.

    abstract::Graphene possesses a wide range of potential biomedical applications because of the unique physical and chemical properties. However, the side effects of grapheme and its derivatives on a number of biological models even on human body are still not very clear. Therefore, to properly assess the potential risk of graphe...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Xu C,Wang J,Xu Y,Shang G,Wang R,Lin Y

    更新日期:2013-10-01 00:00:00

  • The Effects of Genetic Polymorphisms in Pharmacokinetics and Pharmacodynamics Parameters.

    abstract:: ...

    journal_title:Current drug metabolism

    pub_type: 社论


    authors: Wei JF

    更新日期:2018-01-01 00:00:00

  • The role of organic ion transporters in drug disposition: an update.

    abstract::Transporters for organic anions and organic cations in kidney, liver, intestine, brain, and placenta play essential roles in drug disposition. The cloning and characterization of these transporters have significantly advanced our understanding of the molecular and cellular mechanisms of the drug disposition process. T...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: You G

    更新日期:2004-02-01 00:00:00

  • Herb-Drug Interactions and Hepatotoxicity.

    abstract:BACKGROUND:In recent times, herbals or phytomedicines have become very popular due to their global acceptance as a complementary and alternative remedy. While modern drugs are commercially available only after laboratory validations, clinical trials, as well as approval from drug regulatory authorities, majority of the...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Parvez MK,Rishi V

    更新日期:2019-01-01 00:00:00

  • Decreasing systemic toxicity via transdermal delivery of anticancer drugs.

    abstract::When used at a high dose, many anticancer drugs produce undesirable side effects including hepatotoxicity. Transdermal delivery bypasses first-pass metabolism, allowing the use of a lower dose of drug while decreasing systemic toxicity. In this review, we summarize various advanced technologies for improving anticance...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Fang JY,Liu PF,Huang CM

    更新日期:2008-09-01 00:00:00

  • Interactions of liposomes with cells in vitro and in vivo: opsonins and receptors.

    abstract::A number of studies have appeared recently on the underlying mechanisms of liposome-cell interactions under in vitro conditions, in which isolated cell populations or cell lines were used. However, our knowledge of how liposomes interact with cells and the parameters that influence this in vivo is limited. We will sum...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Ishida T,Harashima H,Kiwada H

    更新日期:2001-12-01 00:00:00

  • Electroporation in DNA vaccination protocols against cancer.

    abstract::Since conventional therapeutic approaches in cancer are highly invasive they hardly prolong patient survival for more than few months. Having the ability to stimulate both cellular and humoural immune responses, immunisation with naked plasmid DNA encoding tumour-associated antigens or tumour-specific antigens has rec...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Chiarella P,Fazio VM,Signori E

    更新日期:2013-03-01 00:00:00

  • The impact of in vitro binding on in vitro-in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions.

    abstract::This review provides a vista of the current opportunities and remaining challenges in the area of in vitro-in vivo extrapolation, with particular emphasis on drug binding terms in predictive models, which has been the source of much controversy. Although the importance of fu(inc) (fraction unbound in in vitro incubati...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Grime K,Riley RJ

    更新日期:2006-04-01 00:00:00

  • Nanotechology-based strategies to enhance the efficacy of photodynamic therapy for cancers.

    abstract::Photodynamic therapy (PDT) combines photosensitizer, visible light and oxygen, which has the characteristics of high selectivity, minimal invasiveness, low side effect, and allowing repetitive application. The photophysics and mechanisms leading to cell death mediated by PDT have been studied extensively, and PDT has ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章


    authors: Li WT

    更新日期:2009-10-01 00:00:00

  • Nanoparticles as a Carrier System for Drug Delivery Across Blood Brain Barrier.

    abstract::Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmf...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Sarkar A,Fatima I,Jamal QMS,Sayeed U,Khan MKA,Akhtar S,Kamal MA,Farooqui A,Siddiqui MH

    更新日期:2017-01-01 00:00:00

  • Liver-based in vitro technologies for drug biotransformation studies - a review.

    abstract::Early understanding of the metabolic pathway and potential interaction of new drug candidates with other drugs is one of the goals of preclinical studies in the drug discovery process. Although other body organs are involved in drug biotransformation, the liver is the predominant organ of metabolism for a wide range o...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Fasinu P,Bouic PJ,Rosenkranz B

    更新日期:2012-02-01 00:00:00

  • Impact of various factors on pharmacokinetics of bioactive polyphenols: an overview.

    abstract::Several epidemiological studies throughout the years have suggested that polyphenols from fruits and vegetables promote health and reduce the risk of certain chronic and neurodegenerative diseases. Yet, it has been proved to be extremely difficult to quantitatively establish the benefit afforded by polyphenols, princi...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Rubió L,Macià A,Motilva MJ

    更新日期:2014-01-01 00:00:00

  • Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents.

    abstract::Understanding the mechanism of action of organophosphates (OP)/nerve agents -- irreversible acetylcholinesterase (AChE, EC inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -- two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinerg...

    journal_title:Current drug metabolism

    pub_type: 杂志文章


    authors: Bajgar J,Kuca K,Jun D,Bartosova L,Fusek J

    更新日期:2007-12-01 00:00:00

  • Thiopurine Biotransformation and Pharmacological Effects: Contribution of Oxidative Stress.

    abstract:BACKGROUND:Thiopurine antimetabolites are important agents for the treatment of severe diseases, such as acute lymphoblastic leukemia and inflammatory bowel disease. Their pharmacological actions depend on biotransformation into active thioguanine-nucleotides; intracellular metabolism is mediated by enzymes of the salv...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Pelin M,De Iudicibus S,Londero M,Spizzo R,Dei Rossi S,Martelossi S,Ventura A,Decorti G,Stocco G

    更新日期:2016-01-01 00:00:00

  • Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies.

    abstract::With the advances in recombinant DNA biotechnology, molecular biology and immunology, the number of biotech drugs, including peptides, proteins and monoclonal antibodies, available for clinical use has dramatically increased in recent years. Although pharmacokinetic principles are equally applicable to the large molec...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Lin JH

    更新日期:2009-09-01 00:00:00

  • Characterization of drug interactions with serum proteins by using high-performance affinity chromatography.

    abstract::The binding of drugs with serum proteins can affect the activity, distribution, rate of excretion, and toxicity of pharmaceutical agents in the body. One tool that can be used to quickly analyze and characterize these interactions is high-performance affinity chromatography (HPAC). This review shows how HPAC can be us...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Hage DS,Anguizola J,Barnaby O,Jackson A,Yoo MJ,Papastavros E,Pfaunmiller E,Sobansky M,Tong Z

    更新日期:2011-05-01 00:00:00

  • NF-kappa B signature on the aging wall.

    abstract::During the lifetime, our cells encounter many challenges to their own existence. The survival of organisms and cells depends on the interplay within a complex, yet precisely orchestrated network of proteins. Since the discovery of the Rel/NF-kappaB family of transcription factors, the research has never come to a stop...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Zineldeen DH,Uranishi H,Okamoto T

    更新日期:2010-03-01 00:00:00

  • Gold Nanoparticles: Promising Agent to Improve the Diagnosis and Therapy of Cancer.

    abstract:BACKGROUND:Gold nanoparticles have been exploited for nanobiotechnology applications for the last two decades. New insights of the nanomaterials as promising agent for cancer diagnosis and therapy have just started to emerge. Due to the size- and shape-dependent optical, electrical and thermal properties, gold nanopart...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Ning L,Zhu B,Gao T

    更新日期:2017-01-01 00:00:00

  • In vitro methods to study the interplay of drug metabolism and efflux in the intestine.

    abstract::This review provides an overview of the in vitro methods currently used in studies of intestinal drug metabolism and active efflux with a special emphasis on the efflux- metabolism interplay. These methods include e.g. expressed enzymes or efflux transporters, fractionated intestinal cells, cell lines, primary cells, ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Siissalo S,Heikkinen AT

    更新日期:2013-01-01 00:00:00

  • Nanotechnologies: a strategy to overcome blood-brain barrier.

    abstract::The possibility to treat central nervous system (CNS) disorders is strongly limited by the poor access of many therapeutic agent to the target tissues. This is mainly due to the presence of the blood-brain barrier (BBB), formed by a complex interplay of endothelial cells, astrocyte and pericytes, through which only se...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: De Rosa G,Salzano G,Caraglia M,Abbruzzese A

    更新日期:2012-01-01 00:00:00

  • Effects of dietary broccoli on human in vivo caffeine metabolism: a pilot study on a group of Jordanian volunteers.

    abstract:OBJECTIVES:Induction or inhibition of cytochrome P450 (CYP) enzyme activities, enzymes that activate or detoxify xenobiotics, is one mechanism by which vegetables may alter cancer risk. As the effect of food on CYP enzyme activities have not been studied in the Jordanian population, we examined the effect of supplement...

    journal_title:Current drug metabolism

    pub_type: 临床试验,杂志文章


    authors: Hakooz N,Hamdan I

    更新日期:2007-01-01 00:00:00

  • Clinical utility of acarbose, an alpha-glucosidase inhibitor in cardiometabolic disorders.

    abstract::Diabetes is associated with an increase risk for cardiovascular disease (CVD). Recently, macrovascular complications of diabetes have been shown to start before the development of diabetes. Indeed, several clinical studies have confirmed the increased risk of CVD in patients with impaired glucose tolerance (IGT). Sinc...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Yamagishi S,Matsui T,Ueda S,Fukami K,Okuda S

    更新日期:2009-02-01 00:00:00

  • The gut and intestinal bacteria in chronic heart failure.

    abstract::Chronic heart failure (CHF) is now recognized as a multisystem disorder with increased sympathetic tone, hormonal derangements, an anabolic/catabolic imbalance, endothelial dysfunction, and systemic low-grade inflammation affecting various organ systems. Pro-inflammatory cytokines appear to play important roles in tha...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Sandek A,Anker SD,von Haehling S

    更新日期:2009-01-01 00:00:00

  • Talin: A Potential Drug Target for Cancer Therapy.

    abstract::Talin is an intracellular cytoskeletal protein and one of the major components of the focal adhesion complex. It mainly acts as an interlink between transmembrane integrin receptors and cytosolic F-actin. Apart from integrins and actin, it also interacts with various other proteins in the adhesion complex to regulate ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章


    authors: Malla RR,Vempati RK

    更新日期:2020-01-01 00:00:00

  • Recent Advances in Nanotechnology: A Novel Therapeutic System for the Treatment of Alzheimer's Disease.

    abstract::A amyloid-β (Aβ) plaque formation in the brain is known to be the root cause of Alzheimer's disease (AD), which affects the behavior, memory, and cognitive ability in humans. The brain starts undergoing changes several years before the actual appearance of the symptoms. Nanotechnology could prove to be an alternative ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章


    authors: Chauhan PS,Yadav D,Koul B,Mohanta YK,Jin JO

    更新日期:2020-01-01 00:00:00

  • A review on noscapine, and its impact on heme metabolism.

    abstract::This review introduces the Noscapine, which is being used as an antitussive drug for a long time has been recently discovered as a novel tubulin-binding, anti-angiogenic anticancer drug that causes cell cycle arrest and induces apoptosis in cancer cells both in vitro as well as in vivo. Noscapine is a multifunctional ...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Singh H,Singh P,Kumari K,Chandra A,Dass SK,Chandra R

    更新日期:2013-03-01 00:00:00

  • Heterotropic cooperativity in oxidation mediated by cytochrome p450.

    abstract::Cytochrome P450s (P450 or CYPs) comprise a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals. Although most of P450 inhibitors decrease the metabolic activities mediated by the corresponding P450 forms, unexpected phenomena, which are called as activation or heterotropic coop...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Niwa T,Murayama N,Yamazaki H

    更新日期:2008-06-01 00:00:00

  • Role of Interleukin 28B Polymorphisms in Response to Interferon Based Therapy for Hepatitis C Virus Clearance.

    abstract:BACKGROUND:Interleukin-28B (IL28B) locus on a human chromosomal region mapped to 19q13 execute immune defense against viruses. During Hepatitis C Virus (HCV) infection the IL28B has a promising role in deciding the consequence of infection for spontaneous clearance of viruses or causing chronic liver infection. Treatme...

    journal_title:Current drug metabolism

    pub_type: 杂志文章,评审


    authors: Asthana M,Sahu SK,Kumar A,Mohanty S,Chakrabarti S,Das P,Chattopadhya NR,Chatterjee K,Singh SP,Rajasubramaniam S,Choudhuri T

    更新日期:2018-01-01 00:00:00

  • Changes of Transporters and Drug-metabolizing Enzymes in Nephrotic Syndrome.

    abstract:BACKGROUND:Drug-metabolizing enzymes and transporters play key roles in drug disposition and drug interactions. The alterations of their expression will influence drug pharmacokinetics and pharmacodynamics. However, the changes in the expression of enzymes and transporters in the disease state are still unclear. OBJEC...

    journal_title:Current drug metabolism

    pub_type: 杂志文章


    authors: Dong Y,Gong L,Lu X,Ye M,Lin Y,Xie S,Zhang J,Zhou F,Tang L,Zou W,Liu M

    更新日期:2020-01-01 00:00:00