基于片段的药物设计方法研究进展

基于片段的药物设计(FBDD)已经逐渐发展成为一种重要的药物设计新方法。FBDD利用表面等离子共振技术(SPR)、核磁共振技术(NMR)、质谱(MS)和X-射线单晶衍射等方法检测与靶蛋白相互作用的小分子片段,然后以片段为起点来设计先导化合物。与传统的药物设计方法相比,FBDD具有发现活性化合物效率高的特点,且发现的化合物具有活性强、类药性好等优点。该文结合实例综述了基于片段的药物设计方法的研究进展。     

Fragment-based drug discovery using the SHAPES method

The SHAPES method is one of several fragment-based drug discovery methods developed in the last decade. Molecules containing drug-like fragments are screened using NMR methods to find weakly binding (0.1 μM to multi-mM) hits that are then transformed into potent, viable leads. This review analyzes ten years of SHAPES screens, in which potent leads were found for 70 – 80% of the targets screened, and discusses lessons learned about how best to apply fragment-based lead discovery in the pharmaceutical environment. Detailed examples of lead discovery and optimization for the kinases REDK and MK2 are given. Finally, future directions are considered and a strategy is proposed for increasing efficiency by coupling fragment-based screening with receptor-assisted inhibitor design (NMR-RAID).     

Targeting cancer using fragment based drug discovery

Over the past decade, fragment-based drug discovery has developed significantly and has gained increasing popularity in the pharmaceutical industry as a powerful alternative and complement to traditional high-throughput screening approaches for hit identification. Fragment-based methods are capable of rapidly identifying starting points for structure-based drug design from relatively small libraries of low molecular weight compounds. The main constraints are the need for sensitive methods that can reliably detect the typically weak interactions between fragments and the target protein, and strategies for transforming fragments into higher molecular weight drug candidates. This approach has recently been validated as series of compounds from various programs have entered clinical trials.     

The synergy between combinatorial chemistry and high-throughput screening

Despite the initial promise of combinatorial chemistry, particularly large library combinatorial chemistry, to greatly accelerate drug discovery, this approach has not been fully utilized as a means to build the compound collections of pharmaceutical and biotechnology companies. This review highlights some of the strengths of large library combinatorial chemistry as a means of generating molecules for lead discovery, such as providing rich and robust structure-activity relationships around each hit series. The challenges and concepts emerging from traditional high-throughput screening and fragment-based drug design, how these methods influence the design of large combinatorial libraries and the interpretation of the ensuing high-throughput screening data are also highlighted.     

From laptop to benchtop to bedside: structure-based drug design on protein targets

As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting proteinligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/ optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches.     

Advances in the identification of β-secretase inhibitors

Introduction: Alzheimer's disease (AD), which is characterized by progressive intellectual deterioration, is the most common cause of dementia. β-Secretase (or BACE1) expression is a trigger for amyloid β peptide formation, a cause of AD, and thus is a molecular target for the development of drugs against AD. Many BACE1 inhibitors have been identified by academic and pharmaceutical research groups and a number of advanced technologies in drug discovery have been applied to the drug discovery.

Areas covered: The purpose of this review is to present and discuss the methodologies used for BACE1 inhibitor drug discovery via substrate- and structure-based design, high-throughput screening and fragment-based drug design. The authors also review the advantages and disadvantages of these methodologies.

Expert opinion: Many BACE1 inhibitors have been designed using X-ray crystal structure-based drug design as well as through in silico screening. Nevertheless, there are serious problems with regards to deciding the best X-ray crystal structure for designing BACE1 inhibitors through computational approaches. There are two prominent configurations of BACE1 but there is still room for improvement. Future developments may make it possible to identify BACE1 inhibitors as potential drug candidates.     

The role of fragment-based and computational methods in polypharmacology

Polypharmacology-based strategies are gaining increased attention as a novel approach to obtaining potentially innovative medicines for multifactorial diseases. However, some within the pharmaceutical community have resisted these strategies because they can be resource-hungry in the early stages of the drug discovery process. Here, we report on fragment-based and computational methods that might accelerate and optimize the discovery of multitarget drugs. In particular, we illustrate that fragment-based approaches can be particularly suited for polypharmacology, owing to the inherent promiscuous nature of fragments. In parallel, we explain how computer-assisted protocols can provide invaluable insights into how to unveil compounds theoretically able to bind to more than one protein. Furthermore, several pragmatic aspects related to the use of these approaches are covered, thus offering the reader practical insights on multitarget-oriented drug discovery projects.     

Fragment-based drug discovery: what has it achieved so far?

Fragment-based drug discovery has proved to be a very useful approach particularly in the hit-to-lead process, providing a complementary tool to traditional high-throughput screening. Although often synonymous with fragment screening, fragment-based drug discovery is a far wider area covering high-throughput screening, fragment screening and virtual screening efforts. The unifying feature of fragment-based drug discovery is the low molecular weight of the hit rather than the approach it originates from. Over the last ten years, fragment-based drug discovery has provided in excess of 50 examples of small molecule hits that have been successfully advanced to leads and therefore resulted in useful substrate for drug discovery programs. To our knowledge, there are currently no marketed drugs that can be attributed to these efforts. However, due to the time scales of drug discovery and development it is likely that over the next few years the number of such examples will increase significantly.     

Discovery of modulators of protein-protein interactions: current approaches and limitations

Protein-protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them interesting targets for drug discovery. However, due to the lack of deep pockets, and the large contact surfaces involved in these interactions, they are considered challenging targets and have been often times dismissed as "undruggable". Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This article provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. In addition, examples of successful discovery of modulators of protein-protein interactions are discussed for each of those strategies.     

Virtual screening and its integration with modern drug design technologies

Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics- and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure- and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.     

Rational approaches to natural-product-based drug design

Natural-product-based drug discovery has encountered significant challenges during the past decade. In recent years the pharmaceutical industry has placed low emphasis on natural-product-based drug discovery efforts because of an increasing reliance on newer technologies, such as combinatorial synthesis and high-throughput screening, and their associated approaches to drug discovery. However, recent natural-product-based lead-identifying strategies have successfully and rapidly integrated rational approaches that exploit and evolve the structural diversity provided by nature. These rational approaches include the application of structure- and ligand-based design, relationship building between biosynthetic enzymes and targets as well as within the target and natural product scaffold space, and biology-oriented synthesis-guided library design. This review focuses on the recent clinical and preclinical development of natural-product-based compounds derived from these rational approaches, and is organized according to disease areas as well as novel concepts that may provide a rational basis for future developments.     

Microdispensing technologies in drug discovery

Because of the advent of managed care,the pharmaceutical industry is entering a new era, characterized by increased competition and pricing pressures. As a result, drug discovery within pharmaceutical companies is rapidly embracing new paradigms to help bring more novel drugs to the market as rapidly as possible. One paradigm currently being pursued is the miniaturization of the processes involved in the exploratory phase of drug discovery. This reduction in scale has led to the development of new dispensing technologies. This review examines several microdispensing technologies for drug discovery.     

Recent advances in inkjet dispensing technologies: applications in drug discovery

Introduction: Inkjet dispensing technology is a promising fabrication methodology widely applied in drug discovery. The automated programmable characteristics and high-throughput efficiency makes this approach potentially very useful in miniaturizing the design patterns for assays and drug screening. Various custom-made inkjet dispensing systems as well as specialized bio-ink and substrates have been developed and applied to fulfill the increasing demands of basic drug discovery studies. The incorporation of other modern technologies has further exploited the potential of inkjet dispensing technology in drug discovery and development. Areas covered: This paper reviews and discusses the recent developments and practical applications of inkjet dispensing technology in several areas of drug discovery and development including fundamental assays of cells and proteins, microarrays, biosensors, tissue engineering, basic biological and pharmaceutical studies. Expert opinion: Progression in a number of areas of research including biomaterials, inkjet mechanical systems and modern analytical techniques as well as the exploration and accumulation of profound biological knowledge has enabled different inkjet dispensing technologies to be developed and adapted for high-throughput pattern fabrication and miniaturization. This in turn presents a great opportunity to propel inkjet dispensing technology into drug discovery.     

Current topics in computer-aided drug design

The addition of computer-aided drug design (CADD) technologies to the research and drug discovery approaches could lead to a reduction of up to 50% in the cost of drug design. Designing a drug is the process of finding or creating a molecule which has a specific activity on a biological organism. Development and drug discovery is a time-consuming, expensive, and interdisciplinary process whereas scientific advancements during the past two decades have altered the way pharmaceutical research produces new bioactive molecules. Advances in computational techniques and hardware solutions have enabled in silico methods to speed up lead optimization and identification. We will review current topics in computer-aided molecular design underscoring some of the most recent approaches and interdisciplinary processes. We will discuss some of the most efficient pathways and design.     

Fragment-based screening with natural products for novel anti-parasitic disease drug discovery

ABSTRACT

Introduction: Fragment-based drug discovery can identify relatively simple compounds with low binding affinity due to fewer binding interactions with protein targets. FBDD reduces the library size and provides simpler starting points for subsequent chemical optimization of initial hits. A much greater proportion of chemical space can be sampled in fragment-based screening compared to larger molecules with typical molecular weights (MWs) of 250–500 g mol^?1 used in high-throughput screening (HTS) libraries.

Areas covered: The authors cover the role of natural products in fragment-based drug discovery against parasitic disease targets. They review the approaches to develop fragment-based libraries either using natural products or natural product-like compounds. The authors present approaches to fragment-based drug discovery against parasitic diseases and compare these libraries with the 3D attributes of natural products.

Expert opinion: To effectively use the three-dimensional properties and the chemical diversity of natural products in fragment-based drug discovery against parasitic diseases, there needs to be a mind-shift. Library design, in the medicinal chemistry area, has acknowledged that escaping flat-land is very important to increase the chances of clinical success. Attempts to increase sp³ richness in fragment libraries are acknowledged. Sufficient low molecular weight natural products are known to create true natural product fragment libraries.     

Fragment-based drug design: combining philosophy with technology

Fragment-based drug design began more than ten years ago and has been steadily gaining in popularity. This review discusses how fragments have been used to choose druggable targets, and what parameters need to be evaluated if a fragment hit is to be considered a suitable ligand for development. Examples of fragment-based screening from the recent literature are reviewed to highlight the various approaches used, along with the possible application of additional techniques to fragment screening against immobilized targets. Finally, mention is made of two different areas, multi-target drug discovery and selective tumor cell targeting, where fragment-based approaches may play an important role in the future.     

The Growing Importance of Chirality in 3D Chemical Space Exploration and Modern Drug Discovery Approaches for Hit-ID: Topical Innovations

Modern-day drug discovery is now blessed with a wide range of high-throughput hit identification (hit-ID) strategies that have been successfully validated in recent years, with particular success coming from high-throughput screening, fragment-based lead discovery, and DNA-encoded library screening. As screening efficiency and throughput increases, this enables the viable exploration of increasingly complex three-dimensional (3D) chemical structure space, with a realistic chance of identifying highly specific hit ligands with increased target specificity and reduced attrition rates in preclinical and clinical development. This minireview will explore the impact of an improved design of multifunctionalized, sp³-rich, stereodefined scaffolds on the (virtual) exploration of 3D chemical space and the specific requirements for different hit-ID technologies.     

Electron density guided fragment-based lead discovery of ketohexokinase inhibitors

A fragment-based drug design paradigm has been successfully applied in the discovery of lead series of ketohexokinase inhibitors. The paradigm consists of three iterations of design, synthesis, and X-ray crystallographic screening to progress low molecular weight fragments to leadlike compounds. Applying electron density of fragments within the protein binding site as defined by X-ray crystallography, one can generate target specific leads without the use of affinity data. Our approach contrasts with most fragment-based drug design methodology where solution activity is a main design guide. Herein we describe the discovery of submicromolar ketohexokinase inhibitors with promising druglike properties.     

Design of chemical libraries for screening

Importance of the field: The ultimate goal of discovery screening is to have a fast and cost-effective strategy to meet the demands of producing high-content lead series with improved prospects for clinical success. While high-throughput screening (HTS) dominates the drug discovery landscape, other processes and technologies have emerged, including high-content screening and fragment-based design to provide alternatives that may be more suitable for certain targets. There has been a growing interest in reducing the number of compounds to be screened to prevent the escalation in the costs, time and resources associated with HTS campaigns. Library design plays a central role in these efforts.

Areas covered in this review: This opinion provides a survey of some recent developments in the diversity based library design process, but within a historical context. In particular, the importance of chemotyping and substructure analysis and the challenges presented by novel lead discovery technologies that require the design of libraries for screening are discussed.

What the reader will gain: Readers will gain an appreciation of some developments in the field of library design and the factors that are driving the development of new library design technologies; specifically, challenges presented for chemoinformatics with the novel screening technologies in diversity based screening and compound filtering.

Take home message: Chemotyping and substrutural analysis are techniques that have been underutilized in the process of library design. However, they offer a direct way to evaluate libraries and have been successfully used to develop predictive methodologies. Tools are available to this end, but the full power of the approach has not been realized yet.