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.     

Molecular modeling and computer aided drug design. Examples of their applications in medicinal chemistry

The development of new drugs with potential therapeutic applications is one of the most complex and difficult process in the pharmaceutical industry. Millions of dollars and man-hours are devoted to the discovery of new therapeutical agents. As, the activity of a drug is the result of a multitude of factors such as bioavailability, toxicity and metabolism, rational drug design has been utopias for centuries. Very recently, impressive technological advances in areas such as structural characterization of biomacromolecules, computer sciences and molecular biology have made rational drug design feasible. The aim of this review is to give an outline of studies in the field of medicinal chemistry in which molecular modeling has helped in the discovery process of new drugs. The emphasis will be on lead generation and optimization.     

Toward Rational Fragment-Based Lead Design without 3D Structures

Fragment-based lead discovery (FBLD) has become a prime component of the armamentarium of modern drug design programs. FBLD identifies low molecular weight ligands that weakly bind to important biological targets. Three-dimensional structural information about the binding mode is provided by X-ray crystallography or NMR spectroscopy and is subsequently used to improve the lead compounds. Despite tremendous success rates, FBLD relies on the availability of high-resolution structural information, still a bottleneck in drug discovery programs. To overcome these limitations, we recently demonstrated that the meta-structure approach provides an alternative route to rational lead identification in cases where no 3D structure information about the biological target is available. Combined with information-rich NMR data, this strategy provides valuable information for lead development programs. We demonstrate with several examples the feasibility of the combined NMR and meta-structure approach to devise a rational strategy for fragment evolution without resorting to highly resolved protein complex structures.     

药物重定位候选药物筛选路径

相对传统新药研发模式,药物重定位策略发现药物新用途具有显著的成本效益优势,能加快药物上市步伐,满足恶性肿瘤、罕见病、个性化医疗等特定领域药物临床用药需求,因而被各界关注。本文主要介绍了药物重定位的一般流程与候选药物筛选路径,如从非理性设计方法向基于相似性、基于结构虚拟筛选、推理与机器学习等理性设计方法发现重定位药物的系统性转变。     

Application of high-throughput, molecular-targeted screening to anticancer drug discovery

Increasing insight into the genetics and molecular biology of cancer has resulted in the identification of an increasing number of potential molecular targets for anti-cancer drug discovery and development. These targets can be approached through exploitation of emerging structural biology, "rational" drug design, screening of chemical libraries, or a combination of these methods. In this article we discuss the application of high-throughput screening to anti-cancer drug discovery, with special reference to approaches used at the U.S. National Cancer Institute.     

Insights for the development of specific kinase inhibitors by targeted structural genomics

Many protein kinases are validated intervention points for drug development, however active site similarities often lead to a lack of selectivity and unwanted side effects in the clinic. To address this issue, it is desirable to increase the number of high resolution crystal structures and complexes with non-adenosine ligands available for the rational design of more selective inhibitors. Recent progress in protein crystallography and biotechnology has enabled structural genomics projects to target challenging proteins successfully, including protein kinases. As we discuss here, this effort has resulted in a considerable increase in the number of available high resolution structures and inhibitor complexes and has identified novel structural motifs that are available for drug development.     

Protein models in drug discovery

Over the last few years, the utilization of protein structural information in drug discovery research has matured and is today applied throughout the process, ranging from genomics-derived target identification and selection to the final design of suitable drug candidates. An especially powerful methodology has arisen from the clear synergies of the combination of target structural information with combinatorial chemistry. Several structural genomics initiatives have recently been started and are now generating 3-D structures of target molecules at an unprecedented rate that will provide a wealth of novel information that can be utilized for rational drug design.     

Rational targeting of peroxisome proliferating activated receptor subtypes

Peroxisome-Proliferating Activating Receptors (PPARs) have long been established as validated targets for therapeutic intervention in several important disease states, including type II diabetes and dyslipidemia. More recently, evidence has implicated novel regulatory roles for PPARs in cancer, inflammation and neurodegeneration. Although current PPAR targeting treatments exist, most are associated with undesirable and potentially life-threatening side effects. Consequent from these observations is a significant research effort into PPAR modulator drug discovery and design. In this review, the progress of PPAR modulator design over the past several years will be highlighted. Particular focus on how detailed structural information and virtual screening techniques can aid in the rational design and development of tailored next generation PPAR drug therapeutics will be discussed.     

降胆固醇药Ezetimibe的发现--基于受体外的药物设计新方法

综述新型降胆固醇药Ezetimibe的设计与发现,着重介绍对其先导物SCH48461及体内代谢物的药理活性研究和基于SCH48461活性代谢物及软、硬药理论的药物设计过程,展现了一种完全脱离受体模型、基于受体外的药物设计新方法。     

Indole/isatin-containing hybrids as potential antibacterial agents

The emergence and worldwide spread of drug-resistant bacteria have already posed a serious threat to human life, creating the urgent need to develop potent and novel antibacterial drug candidates with high efficacy. Indole and isatin (indole-2,3-dione) present a wide structural and mechanistic diversity, so their derivatives possess various pharmacological properties and occupy a salient place in the development of new drugs. Indole/isatin-containing hybrids, which demonstrate a promising activity against a panel of clinically important Gram-positive and Gram-negative bacteria, are privileged scaffolds for the discovery of novel antibacterial candidates. This review, covering articles published between January 2015 and May 2020, focuses on the development and structure–activity relationship (SAR) of indole/isatin-containing hybrids with potential application for fighting bacterial infections, to facilitate further rational design of novel drug candidates.     

In silico pathway analysis: the final frontier towards completely rational drug design

Pathway and network analyses are rapidly becoming the mainstream tools for functional interpretation of high-throughput data and for drug discovery. Current scientific literature has plenty of examples on how pathway analysis tools are used across all steps of drug development pipeline. Pathway and network analyses already enable rational selection of drug targets based on the knowledge about disease biology. Pathway analysis tools are also popular for the analysis of drug action and validation of drug efficacy and toxicity. This article overviews current achievements of pathway analysis and suggests future directions for its application in drug development such as rational design of combinatorial therapy and personalized medicine.     

Interference with redox-active enzymes as a basis for the design of antimalarial drugs

Antimalarial drugs are urgently and continuously required. Parasite enzymes involved in antioxidant defence represent interesting target molecules for rational drug development. Here we summarize the currently available data on structural, biochemical, and functional properties of these proteins in an attempt to evaluate and compare their potential as drug targets.     

Protein synthesis as a target for antibacterial drugs: current status and future opportunities

The discovery and development of clinically useful antibiotic classes, such as the aminoglycosides, macrolides and tetracyclines, have clearly demonstrated that bacterial protein synthesis is a suitable target for drug intervention. New information on the binding of classical protein synthesis inhibitors to ribosomal RNA provides a rational explanation for their selective action against bacteria and also explains why chromosomal point mutations conferring resistance by structural changes at the target site are relatively rare in the majority of bacteria. These principles will be helpful when considering strategies for the screening or design of novel protein synthesis inhibitors that could be developed as new antibiotics. Recent progress in the discovery and development of bacterial protein synthesis inhibitors is illustrated by consideration of the glycylcyclines, ketolides, oxazolidinones and streptogramins.     

Pathway analysis for design of promiscuous drugs and selective drug mixtures

The decrease in the drug approval rate by the FDA and the recent failure of some blockbuster drugs has prompted a re-examination of the focus of the pharmaceutical industry on increasing drug selectivity. As a result, it has been proposed that the most efficient cure is in developing promiscuous drugs and selective drug mixtures. Rational design of drug mixtures has been nearly impossible due to the lack of information about in vivo cell regulation, mechanisms of pathway activation, and interactions between different pathways in vivo. We review the current state of the art for rational design of combination therapy and argue that the current industry-wide development of the infrastructure for pathway analysis provides unprecedented opportunity for the rational design of multicomponent and multifunctional drugs. We propose several ways how to use pathway analysis to rationally combine known drugs for either synergizing their efficacy or suppressing individual side effects.     

Combinatorial design of biomaterials for drug delivery: opportunities and challenges

Background: The rational design of biodegradable polymeric devices for controlled drug delivery and tissue engineering is an important area of research for advancing new therapies for cancer, diabetes and immune-related disorders. In an era of escalating costs for discovery-based research, there is an urgent need to develop new and rapid methods to design drug delivery systems. Objective/methods: By merging this field of study with rapid and high throughput methods of design, optimization and development, researchers have been able to accelerate the discovery and design processes for these devices. Combinatorial research enables the rapid identification of key regions of interest. Conclusion: This review focuses on the opportunities and challenges in the area of combinatorial biomaterials design for drug delivery, as there has been a great deal of significant progress over the past decade to propel this approach for the rational design of biomaterials.     

多靶点配体与药物设计

综述有关多靶点配体药物设计的基本原理和方法,包括整合共有药效团法、轭合药效团法、可分解轭合药效团法及筛选法;并讨论多靶点配体与合理药物设计的关系以及设计中应注意的问题,为新药的研究与开发提供参考。     

The hunt for antimitotic agents: an overview of structure-based design strategies

ABSTRACT

Introduction: Structure-based drug discovery offers a rational approach for the design and development of novel anti-mitotic agents which target specific proteins involved in mitosis. This strategy has paved the way for development of a new generation of chemotypes which selectively interfere with the target proteins. The interference of these anti-mitotic targets implicated in diverse stages of mitotic cell cycle progression culminates in cancer cell apoptosis.

Areas covered: This review covers the various mitotic inhibitors developed against validated mitotic checkpoint protein targets using structure-based design and optimization strategies. The protein-ligand interactions and the insights gained from these studies, culminating in the development of more potent and selective inhibitors, have been presented.

Expert opinion: The advent of structure-based drug design coupled with advances in X-ray crystallography has revolutionized the discovery of candidate lead molecules. The structural insights gleaned from the co-complex protein-drug interactions have provided a new dimension in the design of anti-mitotic molecules to develop drugs with a higher selectivity and specificity profile. Targeting non-catalytic domains has provided an alternate approach to address cross-reactivity and broad selectivity among kinase inhibitors. The elucidation of structures of emerging mitotic drug targets has opened avenues for the design of inhibitors that target cancer.     

Analysis of ligand-macromolecule contacts: computational methods

Due to the many technological advancements in biology and development of new fields such as biotechnology and bioinformatics, our knowledge of cellular functions has been growing rapidly; and Biology has entered the Information Age. Along with the technological advancements has come a rapid increase in identification of biomolecular targets involved in diseases. Recently, structure-based drug design studies have emphasized integration of the clinical, cellular, biochemical, structural, and biophysical knowledge of the target. Due to advances in sequencing the human genome, in chemical synthesis and structure determination of biological targets using X-ray and NMR techniques, and in high-performance computing, many scientists from both experimental and theoretical fields focus on structure-based drug design. As scientists in such wide-ranging disciplines, we must understand the data from and educate one another about the strengths and weaknesses of our various disciplines. Since 1990, we have been using computers to visually evaluate ligand binding. In this review, the author will focus on computational methods that not only visualize but also quantify the nature and strength of ligand-macromolecule contacts. Such quantification can be very useful both for medicinal chemists to design ligands and for molecular biologists to design rational protein design experiments to study the effect of amino acid changes on ligand binding.