Recent Advances in the Chemistry and Biology of Naturally Occurring Antibiotics

Ever since the world‐shaping discovery of penicillin, nature's molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug‐development stories, the overwhelming majority of which have their origin in natural products. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on total synthesis, analogue design, and biological evaluation of molecules with novel mechanisms of action.     

Chemistry and Biology of the Caged Garcinia Xanthones

Natural products have been a great source of many small molecule drugs for various diseases. In spite of recent advances in biochemical engineering and fermentation technologies that allow us to explore microorganisms and the marine environment as alternative sources of drugs, more than 70 % of the current small molecule therapeutics derive their structures from plants used in traditional medicine. Natural‐product‐based drug discovery relies heavily on advances made in the sciences of biology and chemistry. Whereas biology aims to investigate the mode of action of a natural product, chemistry aims to overcome challenges related to its supply, bioactivity, and target selectivity. This review summarizes the explorations of the caged Garcinia xanthones, a family of plant metabolites that possess a unique chemical structure, potent bioactivities, and a promising pharmacology for drug design and development.     

Construction of N-Heterocycles through Cyclization of Tertiary Amines

N-Heterocycles have been found in a large number of natural products, drug molecules, and bioactive compounds, and they thereby play a vital role in diverse research disciplines including drug discovery, organic synthesis, chemical biology, and material science. To this end, the development of new methods and strategies for the construction of N-heterocyclic frameworks is arguably one of the most dynamic and significant research areas in organic synthesis. One of these powerful approaches to the synthesis of N-heterocycles is to establish cyclization reactions based on the transformation of tertiary amines, which has emerged as an attractive research topic. In this Minireview, the significant achievements in the construction of N-heterocycles through cyclization of tertiary amines are highlighted and a comprehensive overview of the rational design, development, and application of these synthetic methods is presented.     

Computer-Aided Drug Design Boosts RAS Inhibitor Discovery

The Rat Sarcoma (RAS) family (NRAS, HRAS, and KRAS) is endowed with GTPase activity to regulate various signaling pathways in ubiquitous animal cells. As proto-oncogenes, RAS mutations can maintain activation, leading to the growth and proliferation of abnormal cells and the development of a variety of human cancers. For the fight against tumors, the discovery of RAS-targeted drugs is of high significance. On the one hand, the structural properties of the RAS protein make it difficult to find inhibitors specifically targeted to it. On the other hand, targeting other molecules in the RAS signaling pathway often leads to severe tissue toxicities due to the lack of disease specificity. However, computer-aided drug design (CADD) can help solve the above problems. As an interdisciplinary approach that combines computational biology with medicinal chemistry, CADD has brought a variety of advances and numerous benefits to drug design, such as the rapid identification of new targets and discovery of new drugs. Based on an overview of RAS features and the history of inhibitor discovery, this review provides insight into the application of mainstream CADD methods to RAS drug design.     

Development of functional protein microarrays for drug discovery: progress and challenges

Functional protein microarrays promise new approaches to address longstanding challenges in drug discovery and development, with applications ranging from target identification to clinical trial design. However, their widespread adoption will be contingent upon a robust ability to develop and manufacture arrays in support of these applications. This review will address the major areas of relevance to the development of functional protein microarrays; protein content, surface chemistry, manufacture and assay development. Successful development will empower multiple drug research applications, help fill future HTS pipelines and guide next generation combinatorial chemistry efforts.     

Tetrodotoxin: History,Biology, and Synthesis

This review provides a comprehensive coverage of the history, biology and chemistry of tetrodotoxin (TTX). It traces the origin of this remarkable molecule all the way back to the ancient Chinese medicine records. The discovery of biological activity, isolation, and a brief overview of structure elucidation are summarized. Next, the biology of TTX is discussed, primarily in the context of its activity in the sodium channels, its anesthetic properties, and its potential use in cancer treatment or drug addiction. Biosynthesis of TTX is covered before the discussion of the total syntheses. All total, formal or partial syntheses are covered but those total syntheses that have been discussed in previous reviews are only briefly summarized. Finally, the synthesis of natural and unnatural derivatives is surveyed, and a conclusion and outlook are provided for this very extensive field of endeavor. To the best of our knowledge the literature coverage is complete up to December 2018.     

Aminoboronic acids and esters: from synthetic challenges to the discovery of unique classes of enzyme inhibitors

Although boronic acids have attracted considerable interest as versatile intermediates in organic synthesis, their contributions in chemical biology and drug discovery programs have long been underestimated. This situation is changing since the beginning of the 2000s, mainly due to significant advances in modern organoborane chemistry and the recent FDA approval of Velcade?, a boropeptide used for multiple myeloma treatment. There is now a significant renewed interest in the design and synthesis of new boron-containing compounds. Due to their close analogy to their carbon counterparts, aminoboronic acids, alone or incorporated at the C-terminal position of a peptide, represent one of the major classes of organoboranes evaluated as potential drug candidates. This critical review aims to provide an overview of the current state of the art in their synthesis and their most relevant biological properties (156 references).     

Lead-oriented synthesis: a new opportunity for synthetic chemistry

The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.     

Current trends in virtual high throughput screening using ligand-based and structure-based methods

High throughput in silico methods have offered the tantalizing potential to drastically accelerate the drug discovery process. Yet despite significant efforts expended by academia, national labs and industry over the years, many of these methods have not lived up to their initial promise of reducing the time and costs associated with the drug discovery enterprise, a process that can typically take over a decade and cost hundreds of millions of dollars from conception to final approval and marketing of a drug. Nevertheless structure-based modeling has become a mainstay of computational biology and medicinal chemistry, helping to leverage our knowledge of the biological target and the chemistry of protein-ligand interactions. While ligand-based methods utilize the chemistry of molecules that are known to bind to the biological target, structure-based drug design methods rely on knowledge of the three-dimensional structure of the target, as obtained through crystallographic, spectroscopic or bioinformatics techniques. Here we review recent developments in the methodology and applications of structure-based and ligand-based methods and target-based chemogenomics in Virtual High Throughput Screening (VHTS), highlighting some case studies of recent applications, as well as current research in further development of these methods. The limitations of these approaches will also be discussed, to give the reader an indication of what might be expected in years to come.     

Molecular designer self-assembling peptides

Chemistry has generally been associated with inorganic and organic syntheses, metal-organic composites, coordinate metal chemistry, catalyses, block copolymer, coating, thin film, industrial surfactants and small-molecule drug development. That is about to change. Chemistry will also expand to the discovery and fabrication of biological and molecular materials with diverse structures, functionalities and utilities. The advent of biotechnology, nanotechnology and nanobiotechnology has accelerated this trend. Nature has selected and evolved numerous molecular architectural motifs at nanometer scale over billions of years for particular functions. These molecular nanomotifs can now be designed for new materials and nanodevices from the bottom up. Chemistry will again harness Nature's enormous power to benefit other disciplines and society. This tutorial review focuses on two self-assembling peptide systems.     

20 years of DNA-encoded chemical libraries

The identification of specific binding molecules is a central problem in chemistry, biology and medicine. Therefore, technologies, which facilitate ligand discovery, may substantially contribute to a better understanding of biological processes and to drug discovery. DNA-encoded chemical libraries represent a new inexpensive tool for the fast and efficient identification of ligands to target proteins of choice. Such libraries consist of collections of organic molecules, covalently linked to a unique DNA tag serving as an amplifiable identification bar code. DNA-encoding enables the in vitro selection of ligands by affinity capture at sub-picomolar concentrations on virtually any target protein of interest, in analogy to established selection methodologies like antibody phage display. Multiple strategies have been investigated by several academic and industrial laboratories for the construction of DNA-encoded chemical libraries comprising up to millions of DNA-encoded compounds. The implementation of next generation high-throughput sequencing enabled the rapid identification of binding molecules from DNA-encoded libraries of unprecedented size. This article reviews the development of DNA-encoded library technology and its evolution into a novel drug discovery tool, commenting on challenges, perspectives and opportunities for the different experimental approaches.     

Nanotechnology: Emerging Tool for Diagnostics and Therapeutics

Nanotechnology is an emerging technology which is an amalgamation of different aspects of science and technology that includes disciplines such as electrical engineering, mechanical engineering, biology, physics, chemistry, and material science. It has potential in the fields of information and communication technology, biotechnology, and medicinal technology. It involves manipulating the dimensions of nanoparticles at an atomic scale to make use of its physical and chemical properties. All these properties are responsible for the wide application of nanoparticles in the field of human health care. Promising new technologies based on nanotechnology are being utilized to improve diverse aspects of medical treatments like diagnostics, imaging, and gene and drug delivery. This review summarizes the most promising nanomaterials and their application in human health.     

Chemogenomics and parasitology: small molecules and cell-based assays to study infectious processes

Infectious diseases caused by protozoan parasites--malaria, sleeping sickness, leishmaniasis, Chagas' disease, toxoplasmosis--remain chronic problems for humanity. We lack vaccines and have limited drug options effective against protozoa. Research into anti-protozoan drugs has accelerated with improved in vitro cultivation methods, enhanced genetic accessibility, completed genome sequences for key protozoa, and increased prominence of protozoan diseases on the agendas of well-resourced public figures and foundations. Concurrent advances in high-throughput screening (HTS) technologies and availability of diverse small molecule libraries offer the promise of accelerated discovery of new drug targets and new drugs that will reduce disease burdens imposed on humanity by parasitic protozoa. We provide a status report on HTS technologies in hand and cell-based assays under development for biological investigations and drug discovery directed toward the three best-characterized parasitic protozoa: Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. We emphasize cell growth assays and new insights into parasite cell biology speeding development of better cell-based assays, useful in primary screens for anti-protozoan drug leads and secondary screens to decipher mechanisms of action of leads identified in growth assays. Small molecules that interfere with specific aspects of protozoan biology, identified in such screens, will be valuable tools for dissecting parasite cell biology and developing anti-protozoan drugs. We discuss potential impacts on drug development of new consortia among academic, corporate, and public partners committed to discovery of new, effective anti-protozoan drugs.     

Chemical Epigenetics: The Impact of Chemical and Chemical Biology Techniques on Bromodomain Target Validation

Epigenetics is currently the focus of intense research interest across a broad range of disciplines due to its importance in a multitude of biological processes and disease states. Epigenetic functions result partly from modification of the nucleobases in DNA and RNA, and/or post‐translational modifications of histone proteins. These modifications are dynamic, with cellular machinery identified to modulate and interpret the marks. Our focus is on bromodomains, which bind to acetylated lysine residues. Progress in the study of bromodomains, and the development of bromodomain ligands, has been rapid. These advances have been underpinned by many disciplines, but chemistry and chemical biology have undoubtedly played a significant role. Herein, we review the key chemistry and chemical biology approaches that have furthered our study of bromodomains, enabled the development of bromodomain ligands, and played a critical role in the validation of bromodomains as therapeutic targets.     

天然产物衍生物化学库的组合合成

天然产物在药物化学和化学生物学中发挥着重要作用。目前,组合化学技术在合成天然产物衍生物化学库中的应用也越来越受到重视。本文综述了近5年来报道的组合合成天然产物衍生物化学库的一些例子。     

Fragment-similarity-based QSAR (FS-QSAR) algorithm for ligand biological activity predictions

Quantitative structure–activity relationship (QSAR) studies are useful computational tools often used in drug discovery research and in many scientific disciplines. In this study, a robust fragment-similarity-based QSAR (FS-QSAR) algorithm was developed to correlate structures with biological activities by integrating fragment-based drug design concept and a multiple linear regression method. Similarity between any pair of training and testing fragments was determined by calculating the difference of lowest or highest eigenvalues of the chemistry space BCUT matrices of corresponding fragments. In addition to the BCUT-similarity function, molecular fingerprint Tanimoto coefficient (Tc) similarity function was also used as an alternative for comparison. For validation studies, the FS-QSAR algorithm was applied to several case studies, including a dataset of COX2 inhibitors and a dataset of cannabinoid CB2 triaryl bis-sulfone antagonist analogues, to build predictive models achieving average coefficient of determination (r ²) of 0.62 and 0.68, respectively. The developed FS-QSAR method is proved to give more accurate predictions than the traditional and one-nearest-neighbour QSAR methods and can be a useful tool in the fragment-based drug discovery for ligand activity prediction.     

Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective

Targeted protein degradation (TPD), the ability to control a proteins fate by triggering its degradation in a highly selective and effective manner, has created tremendous excitement in chemical biology and drug discovery within the past decades. The TPD field is spearheaded by small molecule induced protein degradation with molecular glues and proteolysis targeting chimeras (PROTACs) paving the way to expand the druggable space and to create a new paradigm in drug discovery. However, besides the therapeutic angle of TPD a plethora of novel techniques to modulate and control protein levels have been developed. This enables chemical biologists to better understand protein function and to discover and verify new therapeutic targets. This Review gives a comprehensive overview of chemical biology techniques inducing TPD. It explains the strengths and weaknesses of these methods in the context of drug discovery and discusses their future potential from a medicinal chemist's perspective.     

Metal based drugs: from serendipity to design

The platinum anticancer drug cisplatin has made a major contribution to the treatment of testicular and ovarian cancer. This chance discovery has been the stimulus for research into other metal-based drugs. Inorganic chemistry offers many opportunities for medicinal chemistry, and the discovery of metal-based drugs has moved on from chance discovery to rational drug design. There are however, many challenges associated with the drug discovery and development process. The aim of this review is to provide case histories exemplifying the role of rational drug design in modern inorganic medicinal chemistry in the context of these challenges. The evolution of platinum drugs from cisplatin to third generation drugs is described. The molecular target for the platinum agents is DNA. Alternative molecular targets such as thiol-containing proteins and redox processes are proposed. The example of a simple, safe, efficacious metal-based drug, Fosrenol, is reviewed.     

Chemistry,Biology, and Medicine of the Glycopeptide Antibiotics

The war against infectious bacteria is not over! Although vancomycin and glycopeptide antibiotics have provided a strong last line of defence against many drug-resistant bacteria, their overuse has given rise to more dangerous strains of bacteria. An understanding of the chemistry and biology of these highly complex glycopeptides are destined to play a crucial role in the discovery of new antibiotics.     

Spatiotemporal organization of coacervate microdroplets

Liquid–liquid phase separation (LLPS) has emerged as a new paradigm in the fields of soft matter, colloid chemistry, prebiotic chemistry, and cell biology. As phase separation is a dynamic assembly process, how to spatiotemporally regulate the assembly and disassembly of these micrometre-sized droplets, which are referred as biomolecular condensates in biology is essential for their diverse applications in various disciplines. Herein, we discuss recent advances in the spatiotemporal control of phase separation using different physical tools and external environmental stimuli in bulk solutions and living cells. Specifically, the exploration of phase transition in a compartmentalized protocellular system, which can bridge the gap between synthetic and intracellular LLPS systems, is summarized, and the challenges and future research directions are discussed.