Pharmacologically relevant proteins

The emergence of structure-based drug design as a tool for drug discovery and development has focused increased attention on pharmacologically relevant proteins and the use of their three-dimensional structures to design novel pharmaceutical agents. This review describes recent structural studies of selected macromolecules that have been identified as targets for drug development. Several examples of the successful application of structure-based drug design techniques are also described.     

Applying data mining techniques to library design, lead generation and lead optimization

Many data mining techniques have been applied to activity and ADMET datasets and the resulting models are being used to understand quantitative structure-activity relationships and design new libraries. This review summarizes data mining concepts and discuss their application to library design, lead generation (particularly for sequential screening) and lead optimization (specifically for generating and interpreting QSAR models). Also, this review discusses recent comparative studies between data mining techniques and draws some conclusions about the patterns emerging in the drug discovery data mining field.     

Rational approaches,design strategies,structure activity relationship and mechanistic insights for therapeutic coumarin hybrids

Hybrid molecules, furnished by combining two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery that has attracted substantial traction in the past few years. Naturally occurring scaffolds such as coumarins display a wide spectrum of pharmacological activities including anticancer, antibiotic, antidiabetic and others, by acting on multiple targets. In this view, various coumarin-based hybrids possessing diverse medicinal attributes were synthesized in the last five years by conjugating coumarin moiety with other therapeutic pharmacophores. The current review summarizes the recent development (2014 and onwards) of these pharmacologically active coumarin hybrids and demonstrates rationale behind their design, structure-activity relationships (SAR) and mechanistic studies performed on these hybrid molecules. This review will be beneficial for medicinal chemist and chemical biologist, and in general to the drug discovery community and will facilitate the synthesis and development of novel, potent coumarin hybrid molecules serving as lead molecules for the treatment of complex disorders.     

虚拟筛选与新药发现

虚拟筛选是创新药物研究的新方法和新技术,近年来引起了研究机构和制药公司的高度重视,并且已经成为一种与高通量筛选互补的实用化工具,加入到了创新药物研究的工作流程(pipeline)中。本文介绍国际上虚拟筛选及其在创新药物发现中应用的研究进展,特别介绍了我国这方面研究的状况。     

High-throughput human metabolism and toxicity analysis

Poor drug candidate safety profiles are often identified late in the drug development process, manifesting themselves in the preclinical and clinical phases and significantly contributing to the high cost and low yield of drug discovery. As a result, new tools are needed to accelerate the assessment of drug candidate toxicity and human metabolism earlier in the drug development process, from primary drug candidate screening to lead optimization. Although high-throughput screens exist for much of the discovery phase of drug development, translating such screening techniques into platforms that can accurately mimic the human in vivo response and predict the impact of drug candidates on human toxicology has proven difficult. Nevertheless, some success has been achieved in recent years, which may ultimately yield widespread acceptance in the pharmaceutical industry.     

Structural proteomics in drug discovery

High-throughput, automated or semiautomated methodologies implemented by companies and structural genomics initiatives have accelerated the process of acquiring structural information for proteins via x-ray crystallography. This has enabled the application of structure-based drug design technologies to a variety of new structures that have potential pharmacologic relevance. Although there remain major challenges to applying these approaches more broadly to all classes of drug discovery targets, clearly the continued development and implementation of these structure-based drug design methodologies by the scientific community at large will help to address and provide solutions to these hurdles. The result will be a growing number of protein structures of important pharmacologic targets that will help to streamline the process of identification and optimization of lead compounds for drug development. These lead agonist and antagonist pharmacophores should, in turn, help to alleviate one of the current critical bottlenecks in the drug discovery process; that is, defining the functional relevance of potential novel targets to disease modification. The prospect of generating an increasing number of potential drug candidates will serve to highlight perhaps the most significant future bottleneck for drug development, the cost and complexity of the drug approval process.     

Structural proteomics in drug discovery

High-throughput, automated or semiautomated methodologies implemented by companies and structural genomics initiatives have accelerated the process of acquiring structural information for proteins via x-ray crystallography. This has enabled the application of structure-based drug design technologies to a variety of new structures that have potential pharmacologic relevance. Although there remain major challenges to applying these approaches more broadly to all classes of drug discovery targets, clearly the continued development and implementation of these structure-based drug design methodologies by the scientific community at large will help to address and provide solutions to these hurdles. The result will be a growing number of protein structures of important pharmacologic targets that will help to streamline the process of identification and optimization of lead compounds for drug development. These lead agonist and antagonist pharmacophores should, in turn, help to alleviate one of the current critical bottlenecks in the drug discovery process; that is, defining the functional relevance of potential novel targets to disease modification. The prospect of generating an increasing number of potential drug candidates will serve to highlight perhaps the most significant future bottleneck for drug development, the cost and complexity of the drug approval process.     

Chiral liquid chromatography-tandem mass spectrometric methods for stereoisomeric pharmaceutical determinations

The characterization of the drug metabolism and pharmacokinetic (DMPK) profiles of stereoisomers is a fundamental aspect of the drug discovery and development processes. Therefore, chiral drug bioassays are very important to pharmaceutical and biomedical researchers. The recent developments in chiral liquid chromatography coupled to atmospheric pressure ionization tandem mass spectrometry (LC-API-MS/MS) for the analysis of pharmaceuticals are reviewed. Various ionization techniques including electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and atmospheric photoionization (APPI) interfaced with chiral liquid chromatographic methods are described in terms of their ionization efficiencies, matrix effects and limitations. Examples were selected to demonstrate the applicability of these methods for enantioselective bioanalysis.     

Alchemical free energy methods for drug discovery: progress and challenges

Improved rational drug design methods are needed to lower the cost and increase the success rate of drug discovery and development. Alchemical binding free energy calculations, one potential tool for rational design, have progressed rapidly over the past decade, but still fall short of providing robust tools for pharmaceutical engineering. Recent studies, especially on model receptor systems, have clarified many of the challenges that must be overcome for robust predictions of binding affinity to be useful in rational design. In this review, inspired by a recent joint academic/industry meeting organized by the authors, we discuss these challenges and suggest a number of promising approaches for overcoming them.     

Chemical proteomics and its impact on the drug discovery process

Despite the rapid growth of postgenomic data and fast-paced technology advancement, drug discovery is still a lengthy and difficult process. More effective drug design requires a better understanding of the interaction between drug candidates and their targets/off-targets in various situations. The ability of chemical proteomics to integrate a multiplicity of disciplines enables the direct analysis of protein activities on a proteome-wide scale, which has enormous potential to facilitate drug target elucidation and lead drug verification. Over recent years, chemical proteomics has experienced rapid growth and provided a valuable method for drug target identification and inhibitor discovery. This review introduces basic concepts and technologies of different popular chemical proteomic approaches. It also covers the essential features and recent advances of each approach while underscoring their potentials in drug discovery and development.     

Exploring the chemogenomic knowledge space with annotated chemical libraries

The recent human genome initiatives have led to the discovery of a multitude of genes that are potentially associated with various pathologic conditions and, thus, have opened new horizons in drug discovery. Simultaneously, annotated chemical libraries have emerged as information-rich databases to integrate biological and chemical data. They can be useful for the discovery of new pharmaceutical leads, the validation of new biotargets and the determination of the structural basis of ligand selectivity within target families. Annotated libraries provide a strong information basis for computational design of target-directed combinatorial libraries, which are a key component of modern drug discovery. Today, the rational design of chemical libraries enhanced with chemogenomics data is a new area of progressive research.     

Recent Updates on Corals from Nephtheidae

Marine natural products display a wide range of biological activities, which play a vital role in the innovation of lead compounds for the drug development. Soft corals have been ranked at the top in regard to the discovery of bioactive metabolites with potential pharmaceutical applications. Many of the isolated cembranoids revealed diverse biological activities, such as anticancer, antidiabetic and anti‐osteoporosis. Likewise, sterols from soft corals exhibited interesting biological potential as anti‐inflammatory, antituberculosis and anticancer. Consequently, investigating marine soft corals will definitely lead to the discovery of a large number of chemically varied secondary metabolites with countless bioactivities for possible applications in medicine and pharmaceutical industry. This review provides a complete survey of all metabolites isolated from the family Nephtheidae, from 2011 until November 2018, along with their natural sources and biological potential whenever possible.     

Using NMR for ligand discovery and optimization

Several recent technology-driven advances in the area of NMR have rekindled an interest in the application of the technology to problems in drug discovery and development. A unique aspect of NMR is that it has applicability in broadly different areas of the drug discovery and optimization processes. NMR techniques for screening aimed at the discovery of novel ligands or low molecular weight structures for fragment-based build up procedures are being applied commonly in the industry. Application of NMR in structure-guided drug design and metabonomics are also becoming routine. We present an overview of some of the most recent NMR developments in these areas.     

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.     

Essential ingredients for rational drug design

This short review focuses on three aspects of rational drug design that we consider of utmost importance: the conformation of small molecules in solid form, the conformation of small molecules in solution and lesser studied interactions in protein-ligand complexes. Using examples from recent literature, we will illustrate these different aspects and how they have contributed to the discovery of potent modulators.     

Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve.     

Drug discovery of the future: the implications of the human genome project

The elucidation of the 3.2-gigabase human genome will have various impacts on drug discovery. The number of drug targets will increase by at least one order of magnitude and target validation will become a high-throughput process. To benefit from these opportunities, a theory-based integration of the vast amount of new biological data into models of biological systems is called for. The skills and knowledge required for genome-based drug discovery of the future go beyond the traditional competencies of the pharmaceutical industry. Cooperation with biotechnology firms and research institutions during drug discovery and development will become even more important.     

Drug discovery for malaria: a very challenging and timely endeavor

The prevalence of resistance to known antimalarial drugs has resulted in the expansion of antimalarial drug discovery efforts. Academic and nonprofit institutions are partnering with the pharmaceutical industry to develop new antimalarial drugs. Several new antimalarial agents are undergoing clinical trials, mainly those resurrected from previous antimalarial drug discovery programs. Novel antimalarials are being advanced through the drug development process, of course, with the anticipated high failure rate typical of drug discovery. Many of these are summarized in this review. Mechanisms for funding antimalarial drug discovery and genomic information to aid drug target selection have never been better. It remains to be seen whether ongoing efforts will be sufficient for reducing malaria burden in the developing world.     

Molecular biodiversity and recent analytical developments: A marriage of convenience

Nature has developed an outstanding bio- and molecular diversity as a result of billion years of evolution resulting in a tremendous number of secondary metabolites. Among them a small part has been so far explored for discovery of lead compounds. The lead discovery from natural sources is a technological challenge for the pharmaceutical industry. The bio- and molecular diversity in plants, animals and microorganisms, as sources for new leads, and the remarkable recent developments in NMR, mass spectrometry coupled with advanced separation techniques (LC and GC), high throughput screening, and structure-based virtual screening are discussed in this article.     

Impact of drug discovery on stem cell biology

Despite the rapid technical progress in pharmaceutical industry in the past decade, it is still a great challenge to find new drugs and the situation seems more and more serious. However, the history of pharmaceutical industry clearly indicated that the significance of drug discovery went far beyond providing new drugs. For instance, drugs or candidates could be used as selective probes to reveal novel cellular mechanisms, which is a fundamental tenet of chemical biology. More interestingly, accumulating evidence indicates that drugs and candidates can find important use in stem cell biology. Not only approved drugs but also undeveloped pharmacological agents could serve as efficient agents to regulate stem cell fate. Moreover, the target and activity knowledge accumulated during the drug discovery process will help select the stem cell fate modulators in a rational manner. As the progress in stem cell biology will bring positive influence to drug discovery, it can be expected that the current drug discovery efforts will finally bear great fruits in the future.