Network approaches to drug discovery

Introduction: Advances in genomics technologies are providing a very large amount of data on genome-wide gene expression profiles, protein molecules and their interactions with other macromolecules and metabolites. Molecular interaction networks provide a useful way to capture this complex data and comprehend it. Networks are beginning to be used in drug discovery, in many steps of the modern discovery pipeline, with large-scale molecular networks being particularly useful for the understanding of the molecular basis of the disease. Areas covered: The authors discuss network approaches used for drug target discovery and lead identification in the drug discovery pipeline. By reconstructing networks of targets, drugs and drug candidates as well as gene expression profiles under normal and disease conditions, the paper illustrates how it is possible to find relationships between different diseases, find biomarkers, explore drug repurposing and study emergence of drug resistance. Furthermore, the authors also look at networks which address particular important aspects such as off-target effects, combination-targets, mechanism of drug action and drug safety. Expert opinion: The network approach represents another paradigm shift in drug discovery science. A network approach provides a fresh perspective of understanding important proteins in the context of their cellular environments, providing a rational basis for deriving useful strategies in drug design. Besides drug target identification and inferring mechanism of action, networks enable us to address new ideas that could prove to be extremely useful for new drug discovery, such as drug repositioning, drug synergy, polypharmacology and personalized medicine.

Lexicon-free, novel segmentation of online handwritten indic words

Research in the field of recognizing unlimited vocabulary, online handwritten Indic words is still in its infancy. Most of the focus so far has been in the area of isolated character recognition. In the context of lexicon-free recognition of words, one of the primary issues to be addressed is that of segmentation. As a preliminary attempt, this paper proposes a novel script-independent, lexicon-free method for segmenting online handwritten words to their constituent symbols. Feedback strategies, inspired from neuroscience studies, are proposed for improving the segmentation. The segmentation strategy has been tested on an exhaustive set of 10000 Tamil words collected from a large number of writers. The results show that better segmentation improves the overall recognition performance of the handwriting system.

Surface modification and paclitaxel drug delivery of folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles

Nanoparticles are used for a number of biomedical applications. In this work we report the synthesis of folic acid (FA) modified polyethylene glycol (PEG) functionalized hydroxyapatite (HAp) nanoparticles. The anticancer drug, paclitaxel, is attached to the folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles and the in vitro drug release is analyzed. The surface modification and functionalization is confirmed by Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and UV spectroscopy. The importance of the paper is the investigation of the release behavior of paclitaxel conjugated folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles. The results show an initial rapid release and then a sustained release. (C) 2012 Elsevier B.V. All rights reserved.

A possible connection between antidiabetic and antilipemic properties of psoralea corylifolia seeds and the trace elements present: a LIBS based study

Psoralea corylifolia (PC), a medicinal plant, is used in traditional medicine to treat diabetes. Purpose of the research was to examine the antidiabetic and antilipemic potential of PC and to determine the relationship between its antidiabetic potential and the trace elements present. Wistar rats (150-200 g) with fasting blood glucose (FBG) of 80-110 mg dl(-1)(sub-diabetic) and 150-200 mg dl(-1)(mild diabetic) were selected for the short term antidiabetic studies and severely diabetic rats (FBG > 300 mg dl(-1)) were chosen for the long term antidiabetic and hypolipemic studies of PC seed extract. Laser induced breakdown spectroscopy (LIBS) was used to detect trace elements in the PC extract and the intensity ratios of trace elements were estimated. The dose of 250 mg kg(-1) of PC extract was found to be the most effective in lowering blood glucose level (BGL) of normal, sub, mild and severely diabetic rats during FBG and glucose tolerance test (GTT) studies. Lipid profile studies on severely diabetic rats showed substantial reduction in total cholesterol, triglycerides, very low density lipoprotein, and low density lipoprotein and an increase in the total protein, body weight, high density lipoprotein, and hemoglobin after 28 days of treatment. Significant reduction in urine sugar and protein levels was also observed. LIBS analysis of the PC extract revealed the presence of Mg, Si, Na, K, Ca, Zn and Cl. The study validates the traditional use of PC in the treatment of diabetes and confirms its antilipemic potential. The antidiabetic activity of PC extract may partly be due to the presence of appreciable amounts of insulin potentiating elements like Mg, Ca, and K.

Dual enzyme responsive microcapsules simulating an ``OR'' logic gate for biologically triggered drug delivery applications

Hollow microcapsules capable of disintegrating in response to dual biological stimuli have been synthesized from two FDA approved drug molecules. The capsules fabricated from protamine and chondroitin sulphate disintegrate in the presence of either trypsin or hyaluronidase enzymes, which are documented to be simultaneously over-expressed under some pathological conditions.

Crystal structures and binding studies of atovaquone and its derivatives with cytochrome bc(1): a molecular basis for drug design

Crystal structure of trans-atovaquone (antimalarial drug), its polymorph and its stereoisomer (cis) along with five other derivatives with different functional groups have been analyzed. Based on the conformational features of these compounds and the characteristics of the nature of intermolecular interactions, valuable insights into the atomistic details of protein-inhibitor interactions have been derived by docking studies. Atovaquone and its derivatives pack in the crystal lattice using intermolecular O-H center dot center dot center dot O hydrogen bond dimer motifs supported by surrogate weak interactions including C-H center dot center dot center dot O and C-H center dot center dot center dot Cl hydrogen bonds. The docking results of these molecules with cytochrome bc(1) show preferences to form N-H center dot center dot center dot O, O-H center dot center dot center dot O and O-H center dot center dot center dot Cl hydrogen bonds. The involvement of halogen atoms in the binding pocket appears to be significant and is contrary to the theoretically predicted mechanism of protein-ligand docking reported earlier based on mimicking experimental binding results of stigmatellin with cytochrome bc(1). The significance of subtle energy factors controlled by weak intermolecular interactions appears to play a major role in drug binding.

Molecular dynamics simulations of PPI dendrimer-drug complexes

Dendrimeric nanoparticles are potential drug delivery devices which can enhance the solubility of hydrophobic drugs, thus increasing their bioavailability and sustained release action. A quantitative understanding of the dendrimer-drug interactions can give valuable insight into the solubility and release profile of hydrophobic drug molecules in various solvent conditions. Fully atomistic molecular dynamics (MD) simulations have been performed to study the interactions of G5 PPIEDA (G5 ethylenediamine cored poly(propylene imine)) dendrimer and two well known drugs (Famotidine and Indomethacin) at different pH conditions. The study suggested that at low pH the dendrimer-drug complexes are thermodynamically unstable as compared to neutral and high pH conditions. Calculated Potential of Mean Force (PMF) by umbrella sampling showed that the release of drugs from the dendrimer at low pH is spontaneous, median release at neutral pH and slow release at high pH. In addition, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations were also performed at each umbrella sampling window to identify the various energy contributions. To understand the effect of dendrimer chemistry and topology on the solubility and release profile of drugs, this study is extended to explore the solubility and release profile of phenylbutazone drug complexed with G3 poly(amidoamine) and G4 diaminobutane cored PPI dendrimers. The results indicate that the pH-induced conformational changes in dendrimer, ionization states, dendrimer type and pK(a) of the guest molecules influence the free energy barrier and stability of complexation, and thus regulate drug loading, solubility and release.

Investigational drugs for schizophrenia targeting the dopamine receptor: phase II trials

Introduction: For over half a century now, the dopamine hypothesis has provided the most widely accepted heuristic model linking pathophysiology and treatment in schizophrenia. Despite dopaminergic drugs being available for six decades, this system continues to represent a key target in schizophrenia drug discovery. The present article reviews the scientific rationale for dopaminergic medications historically and the shift in our thinking since, which is clearly reflected in the investigational drugs detailed. Areas covered: We searched for investigational drugs using the key words `dopamine,' `schizophrenia,' and `Phase II' in American and European clinical trial registers (clinicaltrials. gov; clinicaltrialsregister.eu), published articles using National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. We provide a brief description of drugs targeting dopamine synthesis, release or metabolism, and receptors (agonists/partial agonists/antagonists). Expert opinion: There are prominent shifts in how we presently conceptualize schizophrenia and its treatment. Current efforts are not as much focused on developing better antipsychotics but, instead, on treatments that can improve other symptom domains, in particular cognitive and negative. This new era in the pharmacotherapy of schizophrenia moves us away from the older `magic bullet' approach toward a strategy fostering polypharmacy and a more individualized approach shaped by the individual's specific symptom profile.

New solid forms of the anti-HIV drug etravirine: salts, cocrystals, and solubility

Thirteen new solid forms of etravirine were realized in the process of polymorph and cocrystal/salt screening to improve the solubility of this anti-HIV drug. One anhydrous form, five salts (hydrochloride, mesylate, sulfate, besylate, and tosylate), two cocrystals (with adipic acid and 1,3,5-benzenetricarboxylic acid), and five solvates (formic acid, acetic acid, acetonitrile, and 2:1 and 1:1 methanolates) were obtained. The conformational flexibility of etravirine suggests that it can adopt four different conformations, and among these, two are sterically favorable. However, in all 13 solid forms, the active pharmaceutical ingredient (API) was found to adopt just one conformation. Due to the poor aqueous solubility of the API, the solubilities of the salts and cocrystals were measured in a 50% ethanol water mixture at neutral pH. Compared to the salts, the cocrystals were found to be stable and showed an improvement in solubility with time. All the salts were dissociated within an hour, except the tosylate, which showed 50% phase transformation after 1 h of the slurry experiment. A structure property relationship was examined to analyze the solubility behavior of the solid forms.

Gene Transfection in High Serum Levels: Case Studies with New Cholesterol Based Cationic Gemini Lipids

Background: Six new cationic gemini lipids based on cholesterol possessing different positional combinations of hydroxyethyl (-CH2CH2OH) and oligo-oxyethylene -(CH2CH2O)(n)- moieties were synthesized. For comparison the corresponding monomeric lipid was also prepared. Each new cationic lipid was found to form stable, clear suspensions in aqueous media. Methodology/Principal Findings: To understand the nature of the individual lipid aggregates, we have studied the aggregation properties using transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential measurements and X-ray diffraction (XRD). We studied the lipid/DNA complex (lipoplex) formation and the release of the DNA from such lipoplexes using ethidium bromide. These gemini lipids in presence of a helper lipid, 1, 2-dioleoyl phophatidyl ethanol amine (DOPE) showed significant enhancements in the gene transfection compared to several commercially available transfection agents. Cholesterol based gemini having -CH2-CH2-OH groups at the head and one oxyethylene spacer was found to be the most effective lipid, which showed transfection activity even in presence of high serum levels (50%) greater than Effectene, one of the potent commercially available transfecting agents. Most of these geminis protected plasmid DNA remarkably against DNase I in serum, although the degree of stability was found to vary with their structural features. Conclusions/Significance: -OH groups present on the cationic headgroups in combination with oxyethylene linkers on cholesterol based geminis, gave an optimized combination of new genera of gemini lipids possessing high transfection efficiency even in presence of very high percentage of serum. This property makes them preferential transfection reagents for possible in vivo studies.

Laser receptive polyelectrolyte thin films doped with biosynthesized silver nanoparticles for antibacterial coatings and drug delivery applications

We report a simple method to fabricate multifunctional polyelectrolyte thin films to load and deliver the therapeutic drugs. The multilayer thin films were assembled by the electrostatic adsorption of poly (allylamine hydrochloride) (PAH) and dextran sulfate (DS). The silver nanoparticles (Ag NPs) biosynthesized from novel Hybanthus enneaspermus leaf extract as the reducing agent were successfully incorporated into the film. The biosynthesized Ag NPs showed excellent antimicrobial activity against the range of enteropathogens, which could be significantly enhanced when used with commercial antibiotics. The assembled silver nano composite multilayer films showed rupture and deformation when they are exposed to laser. The Ag NPs act as an energy absorption center, locally heat up the film and rupture it under laser treatment. The antibacterial drug, moxifloxacin hydrochloride (MH) was successfully loaded into the multilayer films. The total amount of MH release observed was about 63% which increased to 85% when subjected to laser light exposure. Thus, the polyelectrolyte thin film reported in our study has significant potential in the field of remote activated drug delivery, antibacterial coatings and wound dressings. (C) 2013 Elsevier B.V. All rights reserved.

Polyelectrolyte/silver nanocomposite multilayer films as multifunctional thin film platforms for remote activated protein and drug delivery

We demonstrate a nanoparticle loading protocol to develop a transparent, multifunctional polyelectrolyte multilayer film for externally activated drug and protein delivery. The composite film was designed by alternate adsorption of poly(allylamine hydrochloride) (PAH) and dextran sulfate (DS) on a glass substrate followed by nanoparticle synthesis through a polyol reduction method. The films showed a uniform distribution of spherical silver nanoparticles with an average diameter of 50 +/- 20 nm, which increased to 80 +/- 20 nm when the AgNO3 concentration was increased from 25 to 50 mM. The porous and supramolecular structure of the polyelectrolyte multilayer film was used to immobilize ciprofloxacin hydrochloride (CH) and bovine serum albumin (BSA) within the polymeric network of the film. When exposed to external triggers such as ultrasonication and laser light the loaded films were ruptured and released the loaded BSA and CH. The release of CH is faster than that of BSA due to a higher diffusion rate. Circular dichroism measurements confirmed that there was no significant change in the conformation of released BSA in comparison with native BSA. The fabricated films showed significant antibacterial activity against the bacterial pathogen Staphylococcus aureus. Applications envisioned for such drug-loaded films include drug and vaccine delivery through the transdermal route, antimicrobial or anti-inflammatory coatings on implants and drug-releasing coatings for stents. (C) 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chitosan-dextran sulphate nanocapsule drug delivery system as an effective therapeutic against intraphagosomal pathogen Salmonella

Objectives: The ability to target conventional drugs efficiently inside cells to kill intraphagosomal bacteria has been a major hurdle in treatment of infective diseases. We aimed to develop an efficient drug delivery system for combating infection caused by Salmonella, a well-known intracellular and intraphagosomal pathogen. Chitosan dextran sulphate (CD) nanocapsules were assessed for their efficiency in delivering drugs against Salmonella. Methods: The CD nanocapsules were prepared using the layer-by-layer method and loaded with ciprofloxacin or ceftriaxone. Antibiotic-loaded nanocapsules were analysed in vitro for their ability to enter epithelial and macrophage cells to kill Salmonella. In vivo pharmacokinetics and organ distribution studies were performed to check the efficiency of the delivery system. The in vivo antibacterial activity of free antibiotic and antibiotic loaded into nanocapsules was tested in a murine salmonellosis model. Results: In vitro and in vivo experiments showed that this delivery system can be used effectively to clear Salmonella infection, CD nanocapsules were successfully employed for efficient targeting and killing of the intracellular pathogen at a dosage significantly lower than that of the free antibiotic. The increased retention time of ciprofloxacin in the blood and organs when it was delivered by CD nanocapsules compared with the conventional routes of administration may be the reason underlying the requirement for a reduced dosage and frequency of antibiotic administration. Conclusions: CD nanocapsules can be used as an efficient drug delivery system to treat intraphagosomal pathogens, especially Salmonella infection, This delivery system might be used effectively for other vacuolar pathogens including Mycobacteria, Brucella and Legionella.

Advances in nanomedicines for malaria treatment

Malaria is an infectious disease that mainly affects children and pregnant women from tropical countries. The mortality rate of people infected with malaria per year is enormous and became a public health concern. The main factor that has contributed to the success of malaria proliferation is the increased number of drug resistant parasites. To counteract this trend, research has been done in nanotechnology and nanomedicine, for the development of new biocompatible systems capable of incorporating drugs, lowering the resistance progress, contributing for diagnosis, control and treatment of malaria by target delivery. In this review, we discussed the main problems associated with the spread of malaria and the most recent developments in nanomedicine for anti-malarial drug delivery. (C) 2013 Elsevier B.V. All rights reserved.

Targeting the dopamine receptor in schizophrenia: investigational drugs in Phase III trials

Introduction: Antipsychotic drugs date back to the 1950s and chlorpromazine. Soon after, it was established that blockade of dopamine and, in particular, the D-2 receptor was central to this effect. Dopamine continues to represent a critical line of investigation, although much of the work now focuses on its potential in other symptom domains. Areas covered: A search was carried out for investigational drugs using the key words `dopamine', `schizophrenia' and `Phase III' in an American clinical trial registry (clinicaltrials.gov), published articles using the National Library of Medicine's PubMed database, and supplemented results with a manual search of cross-references and conference abstracts. Drugs were excluded that were already FDA approved. Expert opinion: There remains interest, albeit diminished, in developing better antipsychotic compounds. The greatest enthusiasm currently centres on dopamine's role in negative and cognitive symptom domains. With theories conceptualising hypodopaminergic activity as underlying these deficits, considerable effort is focused on drug strategies that will enhance dopamine activity. Finally, a small body of research is investigating dopaminergic compounds vis-a-vis side-effect treatments. In domains beyond psychosis, however, dopamine arguably is not seen as so central, reflected in considerable research following other lines of investigation.