The TB structural genomics consortium: providing a structural foundation for drug discovery

Structural genomics, the large-scale determination of protein structures, promises to provide a broad structural foundation for drug discovery. The tuberculosis (TB) Structural Genomics Consortium is devoted to encouraging, coordinating, and facilitating the determination of structures of proteins from Mycobacterium tuberculosis and hopes to determine 400 TB protein structures over 5 years. The Consortium has determined structures of 28 proteins from TB to date. These protein structures are already providing a basis for drug discovery efforts.     

The emergence of chemical genomics in drug discovery

The interaction of small organic molecules with proteins and other macromolecules is fundamental to drug action. Chemical genomics employs a combination of chemistry, genomics and informatics to study these drug-target interactions in a systematic and global manner in order to improve the efficiency of the drug discovery process.     

Genetics and genomics in neuropsychopharmacology: the impact on drug discovery and development

Genomics, the complete tabulation of all the genes in an organism, has made a major impact on the organisation of fully-integrated pharmaceutical companies. Drug discovery begins with bioinformatic elucidation of a human sequence encoding a potential drug target, followed by cloning and expression of the gene in a format for high throughput screening. Target validation is aided by reference to homologous genes in subhuman species as well as production of transgenic animals. In contrast, the impact of genetics on neuropsychopharmacology has been modest. It is interesting to compare the experience of genetics in the two major clinical disciplines dealing with disorders of the nervous system. Neurology has been at the forefront of human genetics with over 600 disorders mapped, of which causative mutations have been assigned to about 200 Mendelian disorders, each individually rare. Psychiatric genetics has been based on two log fewer diagnoses use of which has only yielded complex segregation patterns, a plethora of weak associations and no gene assignments. In neither case has genetics resulted in the development of a novel therapeutic agent. However, by refinements in diagnosis and genetic technology the promise for the future is great, not only for drug discovery, but also for subsequent preclinical and clinical development.     

Anticancer drug discovery using chemical genomics

Cancer is the leading cause of death in United States and World wide. Drug discovery and development for cancer therapeutics takes several years before a patient is benefited from a new drug. The average time length from start to finish is approximately 15 years. This time length includes 4-5 years of basic research, discovery, preclinical development and validation studies. Next, it takes approximately 7-10 years for a drug to go through human clinical trials. This time length is too long and need to be shortened to benefit patients quickly from new technologies and product development ideas. Furthermore, with the recent explosion of genomics and proteomics information, it is now becoming difficult to make rapid and logical decisions on hundreds of potential drug targets available. Thus, there is immediate need to develop and integrate tools and technologies that will not only reduce the time length but also the risk of late clinical drug failure. Chemical Genomics is an emerging field in which tools and technologies from biology and chemistry are utilized in a parallel and cyclic fashion very early in the development process. In addition chemical genomics proposes to integrate latest developments in tools and technologies from a variety of modern fields such as combinatorial chemistry, informatics, synthesis chemistries, cell based assays, microarrays, genomics and proteomics tools to accelerate drug discovery and development. Thus, in cancer therapeutics the aim of chemical genomics is not only to reduce the time length of pre-clinical development but also the risk of late clinical failure by making smart decisions early in the process.     

Using natural products for drug discovery: the impact of the genomics era

Introduction: Evolutionarily selected over billions of years for their interactions with biomolecules, natural products have been and continue to be a major source of pharmaceuticals. In the 1990s, pharmaceutical companies scaled down their natural product discovery programs in favor of synthetic chemical libraries due to major challenges such as high rediscovery rates, challenging isolation, and low production titers. Propelled by advances in DNA sequencing and synthetic biology technologies, insights into microbial secondary metabolism provided have inspired a number of strategies to address these challenges.

Areas covered: This review highlights the importance of genomics and metagenomics in natural product discovery, and provides an overview of the technical and conceptual advances that offer unprecedented access to molecules encoded by biosynthetic gene clusters.

Expert opinion: Genomics and metagenomics revealed nature’s remarkable biosynthetic potential and her vast chemical inventory that we can now prioritize and systematically mine for novel chemical scaffolds with desirable bioactivities. Coupled with synthetic biology and genome engineering technologies, significant progress has been made in identifying and predicting the chemical output of biosynthetic gene clusters, as well as in optimizing cluster expression in native and heterologous host systems for the production of pharmaceutically relevant metabolites and their derivatives.     

The impact of microwave synthesis on drug discovery

In the past few years, using microwave energy to heat and drive chemical reactions has become increasingly popular in the medicinal chemistry community. First described 20 years ago, this non-classical heating method has matured from a laboratory curiosity to an established technique that is heavily used in academia and industry. One of the many advantages of using rapid 'microwave flash heating' for chemical synthesis is the dramatic reduction in reaction times--from days and hours to minutes and seconds. As will be discussed here, there are good reasons why many pharmaceutical companies are incorporating microwave chemistry into their drug discovery efforts.     

The impact of combinatorial chemistry on drug discovery

This review will firstly present recent examples in the fields of immobilized arrays and dynamic combinatorial chemistry. The article will then emphasize the impact of combinatorial chemistry on target-focused libraries, demonstrating the usefulness of matrix-formatting for structure-activity relationship analysis and/or the advancement in library design and evaluation.     

Integrating genomics across drug discovery and development

The sequencing of the human genome was an exceptional achievement, but it was not an end in itself as it set the foundation for building new knowledge in biology and medicine. The laborious, multifaceted science of drug discovery and development also draws tremendous benefits from mining the human genome and exploiting the large palette of genomic technologies. This article discusses how diverse genomic tools have been used to date and how they will continue to be utilized in the future to impact drug discovery and development. Integrating genomics across drug discovery and development will undoubtedly help to shorten timelines, increase success rates at all stages and ultimately bring the right drugs to the right patients at the right times.     

Chemical ligands, genomics and drug discovery

The sequencing of the human genome and numerous pathogen genomes has resulted in an explosion of potential drug targets. These targets represent both an unprecedented opportunity and a technological challenge for the pharmaceutical industry. A new strategy is required to initiate small-molecule drug discovery with sets of incompletely characterized, disease-associated proteins. One such strategy is the early application of combinatorial chemistry and other technologies to the discovery of bioactive small-molecule ligands that act on candidate drug targets. Therapeutically active ligands serve to concurrently validate a target and provide lead structures for downstream drug development, thereby accelerating the drug discovery process.     

The growing impact of click chemistry on drug discovery

Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions. The copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen bonding and dipole interactions.     

The impact of microwave-assisted organic chemistry on drug discovery

Microwave-assisted organic synthesis (MAOS) is rapidly becoming recognized as a valuable tool for easing some of the bottlenecks in the drug discovery process. This article outlines the basic principles behind the technology and summarizes the areas in which microwave technology has made an impact, to date.     

The impact of pharmacogenetics and pharmacogenomics on drug discovery

It is widely perceived at present that pharmacogenetics and pharmacogenomics are about to revolutionize the face of medicine. In a more realistic assessment, the implementation of molecular genetics and biology will provide us with better ways to treat illnesses, and has already begun to do so in an incremental and evolutionary fashion. However, it is unlikely to change fundamentally the direction of medical progress. Advances are most likely to be made in the area of pharmacodynamics, as we learn to differentiate broader conventional clinical diagnoses into separate molecular subtypes.     

The promise of structural genomics in the discovery of new antimicrobial agents

Structural Genomics stands out among the emerging fields of proteomics since it influences the drug discovery process at so many points. Recent developments in protein expression technologies, x-ray crystallography and NMR spectroscopy provide the essential elements for high-throughput structure determination platforms. Bioinformatics methods to interrogate the resulting data will provide comprehensive, genome-wide databases of protein structure. Genomic sequencing and methods for high-throughput expression and protein purification are furthest advanced for microbial genes and so these have been the early targets for structural genomics initiatives. The information will be invaluable in understanding gene function, designing broad-spectrum small molecule inhibitors and in better understanding drug-host interactions.     

The impact of parallel chemistry in drug discovery

With the application of parallel synthesis of single compounds to drug-discovery efforts, improvements in the efficiency of synthesis are possible. However, for improvements to occur in effective drug design - a critical requirement to increase productivity in the modern pharmaceutical industry - the implementation of in silico design hypotheses that incorporate comprehensive information on a target, including considerations of absorption, distribution, metabolism and excretion, is also necessary. Concomitantly, the use of automated methods of synthesis and purification is also required to improve drug design. Combining all of these elements allows the possibility to uncover unique insights into a biological target quickly and to therefore accelerate the rate of drug discovery.     

The impact of the Orphan Drug Act on drug discovery

For nearly a quarter of a century the FDA Office of Orphan Products Development has administered the US Orphan Drug Act, which assists in bringing a wide variety of drug and biological (drug) products to treat rare diseases to market. Enthusiasm for rare disease product development has been sustained, seen throughout a wide spectrum of product types and disease conditions, and has resulted in clinically meaningful medical advances. Development of programmes for rare disease treatment worldwide, coupled with the development of drugs for diseases affecting developing countries, attests to the strength of this legislation. The marketing of almost 300 products in the US for rare diseases also testifies to the depth and intensity of scientific endeavour in this area.     

The impact of genetics on future drug discovery in schizophrenia

Introduction: Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations.

Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs.

Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.