The role and future potential of fluorinated biomarkers in positron emission tomography

Importance of the field: Positron emission tomography (PET) is rapidly emerging as the functional imaging method of choice for in vivo imaging applications in a number of key areas of drug discovery and clinical pathology, but especially in oncology. One key limitation of PET is the requirement for rapid synthesis and purification of biomarker/drug molecules regiospecifically labelled with short-lived positron-emitting isotopes. Areas covered in this review: In this review, we focus on the role of (18)F-labelled molecules in PET, presenting a perspective on the challenges associated with the synthesis and future clinical utility of a range of labelled small molecules and macromolecular structures. Further preclinical method development for the regiospecific synthesis of fluorinated biomarkers under mild conditions is required before a wide range of (18)F-labelled molecules take their place alongside clinically established oncology biomarkers such as (18)FDG and (18)FLT. What the reader will gain: In this review, we offer insights into current and future chemical methods for the efficient synthesis of fluorinated PET biomarkers, featuring modern technologies such as microwave-promoted chemistries and microfluidic reactors, both of which possess the capability to routinely and rapidly produce the small quantities of PET-labelled molecules under the mild and efficient conditions that are required for PET tracer synthesis. Take home message: (18)F PET is a flourishing field with many applications in drug discovery and development, through radiolabelling of drug molecules or use of fluorinated disease biomarkers.     

De novo design: balancing novelty and confined chemical space

Importance of the field: De novo drug design serves as a tool for the discovery of new ligands for macromolecular targets as well as optimization of known ligands. Recently developed tools aim to address the multi-objective nature of drug design in an unprecedented manner. Areas covered in this review: This article discusses recent advances in de novo drug design programs and accessory programs used to evaluate compounds post-generation. What the reader will gain: The reader is introduced to the challenges inherent in de novo drug design and will become familiar with current trends in de novo design. Furthermore, the reader will be better prepared to assess the value of a tool, and be equipped to design more elegant tools in the future. Take home message: De novo drug design can assist in the efficient discovery of new compounds with a high affinity for a given target. The inclusion of existing chemoinformatic methods with current structure-based de novo design tools provides a means of enhancing the therapeutic value of these generated compounds.     

Atomic Interactions and Profile of Small Molecules Disrupting Protein–Protein Interfaces: the TIMBAL Database

Growing evidence of the possibility of modulating protein–protein interactions with small molecules is opening the door to new approaches and concepts in drug discovery. In this paper, we describe the creation of TIMBAL, a hand‐curated database holding an up to date collection of small molecules inhibiting multi‐protein complexes. This database has been analysed and profiled in terms of molecular properties. Protein–protein modulators tend to be large lipophilic molecules with few hydrogen bond features. An analysis of TIMBAL’s intersection with other structural databases, including CREDO (protein–small molecule from the PDB) and PICCOLO (protein–protein from the PDB) reveals that TIMBAL molecules tend to form mainly hydrophobic interactions with only a few hydrogen bonding contacts. With respect to potency, TIMBAL molecules are slightly less efficient than an average medicinal chemistry hit or lead. The database provides a resource that will allow further insights into the types of molecules favoured by protein interfaces and provide a background to continuing work in this area. Access at http://www‐cryst.bioc.cam.ac.uk/timbal     

Development of drugs for Epstein-Barr virus using high-throughput in silico virtual screening

Importance of the field: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is causally associated with endemic forms of Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects > 90% of the adult population and is responsible for ～ 1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases. Areas covered in this review: In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes as well as proteins that are expressed exclusively during latent infection, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1. As the atomic structure of the EBNA-1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, such as EBNA-1, to treat EBV infection and disease. What the reader will gain: The reader is familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process. Take home message: Despite the impressive efficacy of nucleoside analogs for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. As EBV latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High-throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease.     

Molecularly imprinted therapeutic contact lenses

Importance of the field: There exists a considerable unmet need for more efficacious delivery of ocular therapeutics. Contact lenses have been developed with high loading and controllable sustained release to overcome limited patient compliance and significant ocular transport limitations. This can best be achieved by extending and controlling the residence time of drugs on the eye surface and thereby limiting drug loss by lacrimation, drainage and non-productive absorption.

Areas covered in the review: Within hydrogels, molecular imprinting can be used to create memory for template molecules embedded within a flexible macromolecular network. Control in therapeutic loading and delay of release have been demonstrated with careful attention to the functional monomer/template ratio, the diversity of functional monomers, and the polymer backbone and network structure. Experimental work has also confirmed that macromolecular memory and not structural differences or phenomena are responsible for delayed drug release kinetics compared with non-imprinted systems. A therapeutically relevant amount of drug can be loaded for release to occur over multiple days, which allows the technique to be applied to daily-wear and extended-wear contact lenses.

What the reader will gain: The focus of this article is to review the emerging field of molecularly imprinted contact lenses and highlight significant accomplishments, trends, as well as future strategies and directions.

Take home message: In the past 8 years, molecular imprinting has been used to produce therapeutic contact lenses with enhanced loading and delayed release. Progress in the field has mostly included low-molecular-weight therapeutics such as anti-glaucoma, antihistamine, antibiotic and anti-inflammatory therapeutics used to treat anterior eye disorders. Recently, high molecular weight comfort molecules have also been successfully demonstrated. Current methods can produce lenses of suitable thickness, water content, and mechanical and optical properties compared with commercial lenses on the market today.     

Current strategies for drug discovery through natural products

Importance to the field: Natural products are the most consistently successful source of drug leads, both historically and currently. Despite this, the use of natural products in industrial drug discovery has fallen out of favour. Natural products are likely to continue to be sources of new commercially viable drug leads because the chemical novelty associated with natural products is higher than that of any other source: this is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads. Areas to be covered: Current drug discovery strategies involving natural products are described in three sections: developments from traditionally used medicines, random testing of natural compounds on biological assays and use of virtual screening techniques with structures of natural products. What the reader will gain: The reader will gain an insight into the potential for natural products in current drug discovery paradigms, particularly in the value of using natural products in virtual screening approaches. Take home message: Drug discovery would be enriched if fuller use was made of the chemistry of natural products.     

Drawing the PDB: Protein?Ligand Complexes in Two Dimensions

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Recent progress in robot-based systems for crystallography and their contribution to drug discovery

Introduction: X-ray crystallography is the main tool for macromolecular structure solution at atomic resolution. It provides key information for the understanding of protein function, opening opportunities for the modulation of enzymatic mechanisms, and protein–ligand interactions. As a consequence, macromolecular crystallography plays an essential role in drug design, as well as in the a posteriori validation of drug mechanisms.

Areas covered: The demand for method developments and also tools for macromolecular crystallography has significantly increased over the past 10 years. As a consequence, access to the facilities required for these investigations, such as synchrotron beamlines, became more difficult and significant efforts were dedicated to the automation of the experimental setup in laboratories. In this article, the authors describe how this was accomplished and how robot-based systems contribute to the enhancement of the macromolecular structure solution pipeline.

Expert opinion: The evolution in robot technology, together with progress in X-ray beam performance and software developments, contributes to a new era in macromolecular X-ray crystallography. Highly integrated experimental environments open new possibilities for crystallography experiments. It is likely that it will also change the way this technique will be used in the future, opening the field to a larger community.     

Carbonic anhydrase inhibition as a cancer therapy: a review of patent literature, 2007 – 2009

Importance of the field: The functional contribution of membrane-bound extracellular carbonic anhydrases (CAs) to hypoxic tumor growth and progression has long been hypothesized; however, recent convergent evidence from a number of groups strongly implicates these CAs as key prosurvival enzymes during tumor hypoxia. From this perspective targeting the inhibition of cancer-associated CA enzymes, most notably CA IX and XII, has recently been identified as a mechanistically novel scientific opportunity with great potential as a new cancer drug target.

Areas covered in this review: This review covers world patent applications filed during the 2007 – 2009 period for small molecule approaches; non-small molecule approaches are not within the scope of this review.

What the reader will gain: The reader will be provided with a background of the biology of CAs as well as the recent research findings that have validated the crucial prosurvival role of CAs in hypoxic tumors. The review will highlight small molecule molecular methods that modulate CAs as an anti-cancer therapeutic strategy.

Take home message: Much of what has been reported in the patent literature during the period 2007 – 2009 is based on alleged therapeutic benefits of CA inhibitors in cancer. Recently appropriate CA-relevant cell and animal models of tumor hypoxia for the evaluation of compounds have become available and the verification of the ability of small molecules to modulate CA activity as a cancer therapy or as a diagnostic and/or prognostic tool is now possible and probable. The CA field will thus provide for a scientifically exciting and possibly rewarding next few years, accelerated by the growing interest in the potential clinical applications of this enzyme class in oncology.     

De novo design: balancing novelty and confined chemical space

Importance of the field: De novo drug design serves as a tool for the discovery of new ligands for macromolecular targets as well as optimization of known ligands. Recently developed tools aim to address the multi-objective nature of drug design in an unprecedented manner.

Areas covered in this review: This article discusses recent advances in de novo drug design programs and accessory programs used to evaluate compounds post-generation.

What the reader will gain: The reader is introduced to the challenges inherent in de novo drug design and will become familiar with current trends in de novo design. Furthermore, the reader will be better prepared to assess the value of a tool, and be equipped to design more elegant tools in the future.

Take home message: De novo drug design can assist in the efficient discovery of new compounds with a high affinity for a given target. The inclusion of existing chemoinformatic methods with current structure-based de novo design tools provides a means of enhancing the therapeutic value of these generated compounds.     

Opportunities and limits of cell-based assay miniaturization in drug discovery

Importance of the field: Miniaturization is a significant driver for many life-science applications and a key technology for personalized medicine. Innovations in microfluidics will make ex vivo testing in in vivo-like environment possible, thus, allowing novel pathways for drug discovery. Areas covered in this review: This review covers the application of miniaturization technologies, namely microfluidics for cell-based assay development. We highlight the use of microfluidics in sample preparation and clinical trials, review the progress towards in vivo-like test environments and point out practical challenges in the work with microfluidic systems. What the reader will gain: The reader will gain an overview of the different application areas of miniaturized systems for cell-based assay-methods and the technologies involved in how they can be applied in the drug discovery process is given. Examples of clinical applications are pointed out. Take home message: Miniaturization is a key technology driver for methodological progress in drug discovery. The enabling nature of this technology is reflected in the multitude of applications covering all aspects of the drug discovery process.     

Development of drugs for Epstein–Barr virus using high-throughput in silico virtual screening

Importance of the field: Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus that is causally associated with endemic forms of Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects > 90% of the adult population and is responsible for ～ 1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases.

Areas covered in this review: In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes as well as proteins that are expressed exclusively during latent infection, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1. As the atomic structure of the EBNA-1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, such as EBNA-1, to treat EBV infection and disease.

What the reader will gain: The reader is familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process.

Take home message: Despite the impressive efficacy of nucleoside analogs for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. As EBV latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High-throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease.     

Current strategies for drug discovery through natural products

Importance to the field: Natural products are the most consistently successful source of drug leads, both historically and currently. Despite this, the use of natural products in industrial drug discovery has fallen out of favour. Natural products are likely to continue to be sources of new commercially viable drug leads because the chemical novelty associated with natural products is higher than that of any other source: this is particularly important when searching for lead molecules against newly discovered targets for which there are no known small molecule leads.

Areas to be covered: Current drug discovery strategies involving natural products are described in three sections: developments from traditionally used medicines, random testing of natural compounds on biological assays and use of virtual screening techniques with structures of natural products.

What the reader will gain: The reader will gain an insight into the potential for natural products in current drug discovery paradigms, particularly in the value of using natural products in virtual screening approaches.

Take home message: Drug discovery would be enriched if fuller use was made of the chemistry of natural products.     

Design of stimuli-responsive dendrimers

Importance of the field: Dendrimers are synthetic macromolecules with well-defined structures, many terminal functional groups, and an inner space to hold small molecules. These properties make them potential drug carriers. Recently, stimuli-responsive drug delivery systems have become attractive because of the reduction of side effects and maximum expression of drug action.

Areas covered in this review: This paper reviews dendrimer nanoparticles that are sensitive to temperature, light, pH and redox state.

What the reader will gain: Strategies to design these dendritic polymers are provided in this review.

Take home message: By adding stimuli-responsive properties to the dendrimers, dendritic polymers capable of controlled release can be produced. These stimuli-responsive dendrimers are a potential next generation drug carrier.     

The alluring potential of functionalized carbon nanotubes in drug discovery

Importance of the field: The possibility of carbon nanotube integration into living systems for therapeutic and diagnostic purposes has opened the way to explore their applications in drug delivery and discovery. A wide variety of chemical approaches has been developed to functionalize carbon nanotubes with therapeutic molecules towards different biomedical uses. Areas covered in this review: This review covers the recent advances in the development of functionalized carbon nanotubes to offer improvements for different diseases, in particular for cancer therapy. What the reader will gain: Functionalized carbon nanotubes are able to transport therapeutic agents. Targeted methodologies using carbon nanotube-based conjugates have been investigated to improve the efficacy of some drugs. The capacity of such nanomaterials to seamlessly translocate into cells with alternative various mechanisms and their pharmacokinetic properties is also discussed. Take home message: Although at its infancy, functionalized carbon nanotubes are very promising as a new nanomedicine platform in the field of drug discovery and delivery. They have the capacity to cross biological barriers and can be eliminated via renal and/or fecal excretion. They can transport small drug molecules while maintaining - and in some cases improving - their therapeutic efficacy.     

Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs

Importance of the field: Transdermal delivery of macromolecules provides an attractive alternative route of drug administration when compared to oral delivery and hypodermic injection because of its ability to bypass the harsh gastrointestinal tract and deliver therapeutics non-invasively. However, the barrier properties of the skin only allow small, hydrophobic permeants to traverse the skin passively, greatly limiting the number of molecules that can be delivered via this route. The use of low-frequency ultrasound for the transdermal delivery of drugs, referred to as low-frequency sonophoresis (LFS), has been shown to increase skin permeability to a wide range of therapeutic compounds, including both hydrophilic molecules and macromolecules. Recent research has demonstrated the feasibility of delivering proteins, hormones, vaccines, liposomes and other nanoparticles through LFS-treated skin. In vivo studies have also established that LFS can act as a physical immunization adjuvant. LFS technology is already clinically available for use with topical anesthetics, with other technologies currently under investigation.

Areas covered in this review: This review provides an overview of mechanisms associated with LFS-mediated transdermal delivery, followed by an in-depth discussion of the current applications of LFS technology for the delivery of hydrophilic drugs and macromolecules, including its use in clinical applications.

What the reader will gain: The reader will gain an insight into the field of LFS-mediated transdermal drug delivery, including how the use of this technology can improve on more traditional drug delivery methods.

Take home message: Ultrasound technology has the potential to impact many more transdermal delivery platforms in the future due to its unique ability to enhance skin permeability in a controlled manner.     

Platforms for the identification of GPCR targets, and of orthosteric and allosteric modulators

Areas covered in this review: The review provides a summary of old and new approaches for GPCR target identification and for the screening of molecules acting on GPCR targets. The new findings in the field are presented as well as an opinion about how these developments may help GPCR drug discovery. Importance in the field: GPCRs have been the most useful family of proteins in terms of targets for drug discovery. The expectations for GPCR target identification and discovery of new drugs acting on 'old' or 'new' GPCR targets are very high. Given the fact that the pace at which new 'GPCR drugs' appear in the market is decreasing and since the new developments in the field are not being translated into drug discovery there is a need to review the field from a critical perspective. Take home message: To overcome the limitation of the old approaches used in GPCR target identification and drugs discovery new approaches are required. In particular successful approaches in GPCR drug discovery should take into account that the real GPCR targets for a given disease are not GPCR monomers but GPCR heteromers. What the reader will gain: The reader will gain an overview of the strategies currently used and their pros and cons. The reader will also understand that new strategies may help in accelerating the access of GPCR into the market, and also notice that successful strategies should take advantage of the new findings in the field of GPCRs.     

Discovery of new small molecules and targets towards angiogenesis via chemical genomics approach

Chemical genetics/genomics is an inter- and multi-disciplinary research engine, which utilizes small molecules to explore the function of genes and accelerate the drug discovery. Bioactive small molecules that are permeable to cellular membrane and bind to its cognate target protein can exert the phenotype changes of the cells or organisms. Functional target proteins of these small molecules have been successfully identified by affinity, genetics and genomics based target identification. The specific molecular recognition of small molecule with target protein has facilitated to decipher the mode of actions of small molecules and developed better drug based on their structure activity relationship. Based on this idea, we have applied chemical genomics to angiogenesis, a new blood vessel formation, resulting in the identification of new small molecules as well as targets. In this review, our application of chemical genomics towards a cellular phenotype, angiogenesis, will be demonstrated.