File Name: target oriented and diversity oriented organic synthesis in drug discovery .zip
Natural products are the source of innumerable pharmaceutical drug candidates and also form an important aspect of herbal remedies.
Chemical Genomics pp Cite as. This article covers the diversity-oriented synthesis DOS of small molecules in order to generate a collection of pure compounds that are attractive for lead generation in a phenotypic, high-throughput screening approach useful for chemical genetics and drug discovery programmes. Nature synthesizes a rich structural diversity of small molecules, however, unfortunately, there are some disadvantages with using natural product sources for diverse small-molecule discovery. Nevertheless we have a lot to learn from nature.
Deficiencies in current compound collections are evidenced by the continuing decline in drug-discovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds.
A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis DOS aims to generate such structural diversity in an efficient manner. Recent years have witnessed significant achievements in the field, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.
Small molecular mass chemical entities so-called small molecules have always been of interest in chemistry and biology because of their ability to exert powerful effects on the functions of macromolecules that comprise living systems 1 , 2 , 3.
Indeed, the small-molecule modulation of protein function represents the basis for both medicinal chemistry wherein molecules are sought to chemically modify disease states and chemical genetics wherein molecules are used as 'probes' to study biological systems 3 , 4 , 5 , 6 , 7 , 8.
Such chemical modulators are most commonly identified by screening collections or 'libraries' of small molecules. However, a crucial consideration is what compounds to use 3 , 9 , A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and more importantly function, is a crucial consideration.
The efficient creation of functionally diverse small-molecule collections presents a formidable challenge. Traditionally, when a specific biological molecule or family of molecules is targeted, the compounds used in the screening process are usually selected or designed on the basis of knowledge of the target structure or the structure of known natural ligands 3 , 9 , The selection criteria are dramatically complicated if the subsequent screening is 'unbiased'; that is, when the precise nature of the biological target is unknown for example, in a random drug-discovery screen 4 , 3 , In such situations, the structural features required in the small molecules cannot be defined a priori and it can be argued that the screening of a library of compounds that has been designed to interact with one specific biological target or family of related targets is not logical, whereas the random screening of many such 'focused' collections can be extremely time and cost demanding.
In general, the identification of biologically active small molecules may be aided by screening functionally diverse compound libraries that is, libraries that display a broad range of biological activities , as it has been argued that a greater sample of the bioactive chemical universe that is, of all bioactive molecules increases the chance of identifying a compound with the desired properties 3 , 10 , 13 , As a corollary, there is a correlation between library functional diversity and the likelihood of identifying small-molecule modulators for a broad range of biological targets in any screening process 10 , This is particularly important in modern chemical biology studies in which rapid advances in genomic and proteomic approaches to drug discovery are expected to lead to an exponential increase in potential therapeutic targets, creating an ever-increasing demand on access to functionally diverse chemical libraries 10 , As the biological activity of any given molecule is intrinsically dependent on its structure, the overall functional diversity of a small-molecule library is directly correlated with its overall structural diversity, which in turn is proportional to the amount of chemical space that the library occupies 3 , 10 , In this review, we comment on various factors associated with efficient creation of functionally diverse small-molecule collections.
In particular, we focus on the development of diversity-oriented synthesis DOS , a synthetic approach that seeks to achieve this goal, primarily through the efficient incorporation of multiple molecular scaffolds in the library. The utility of DOS for the discovery of novel small molecules with exciting biological properties is highlighted.
Finally, future perspectives regarding the use and continued development of DOS are discussed. The term 'diversity' is somewhat subjective.
Nevertheless, there are four principal components of structural diversity that have been consistently identified in literature 3 , 10 , 12 , 17 , 18 :.
Appendage diversity or building-block diversity —variation in structural moieties around a common skeleton;. Stereochemical diversity —variation in the orientation of potential macromolecule-interacting elements;. It is worth emphasizing that the overall shape of a small molecule is the most fundamental factor controlling its biological effects.
Nature 'sees' molecules as three-dimensional 3D surfaces of chemical information; a given biological macromolecule will therefore only interact with those small molecules that have a complementary 3D binding surface 1 , 3 , That is, a given biological macromolecule imposes a degree of shape selection for binding partners; molecules possessing significant shape similarity would thus be expected to generate similar pharmacological responses The molecular shape diversity of a small-molecule library has therefore been cited as being arguably the most fundamental indicator of overall functional diversity; indeed, substantial 'shape space' coverage that is, molecular shape diversity has been correlated with broad biological activity However, it has been demonstrated that the shape space coverage of any compound set stems mainly from the nature and 3D geometries of the central scaffolds, with the peripheral substituents being of minor importance; that is, the scaffold diversity of a small-molecule library has a pivotal role in defining its overall molecular shape diversity Scaffold diversity is thus intrinsically linked to shape, and thus functional, diversity.
Indeed, there is a widespread consensus that increasing the scaffold diversity in a small-molecule library is one of the most effective ways of increasing its overall structural diversity 3 , 10 , 15 , 19 , 21 and small multiple scaffold libraries are generally regarded as being superior to large single-scaffold libraries in terms of biorelevant diversity 3 , 10 , Compounds in libraries that are based around different molecular skeletons will display chemical information differently in 3D space, thus increasing the range of potential biological binding partners for the library as a whole 3.
Although there have been advances in the use of computational methods to assess the overall molecular shape diversity of libraries vide infra , the concept of scaffold diversity is arguably more intuitive to a synthetic chemist and is more conveniently related to synthetic accessibility. Therefore, from a DOS perspective, scaffold diversity serves as a useful surrogate measure for shape diversity and thus overall functional diversity.
In addition to structural diversity, structural complexity is generally regarded as an important characteristic in small-molecule libraries 3 , 10 , It has been argued that molecules that are structurally complex are more likely to interact with biological macromolecules in a selective and specific manner 3 , 9 , 10 , 18 , 23 , 24 , Structurally, and thus functionally, diverse small-molecule libraries should span large regions of biologically relevant chemical space. Consequently, they may prove valuable for the identification of biologically useful small molecules.
However, where does one obtain such collections? Broadly speaking, there are three distinct sources of small molecules for use in biological screens: natural products; commercially available compound collections; or new compound collections created by chemical synthesis 3 , Numerous natural products have proven to be useful as drugs or leads 26 and nature still represents a major source of innovative therapeutic agents 3 , 10 , Natural products exhibit enormous structural diversity, including scaffold diversity 3 , 9 , 10 , However, there are several well-documented problems associated with using natural products in screening experiments including difficulties with purification, bioactive component identification and chemical modification 3 , 9 , 10 , 18 , Commercially available combinatorial libraries and pharmaceutical proprietary compound collections represent important alternative sources of molecules Typically, such collections are comprised of large numbers of structurally simple generally 'flat' and similar compounds, with 'diversity' limited to variations in appendages attached to a small number of common skeletons Consequently, the functional diversity and thus chemical space coverage achieved by such collections is relatively small.
By combining many of these libraries together, a certain degree of chemical diversity can be achieved, such as in the compound archives of large pharmaceutical companies, which typically comprise several million compounds 10 , However, such corporate compound collections are typically heavily biased towards compounds that satisfy certain predefined criteria imposed by the confines of traditional medicinal chemistry-led optimization campaigns for example, Lipinski's 'rule of 5' criteria for orally bioavailable drugs 10 , This has a number of potential drawbacks, especially in the context of identifying novel bioactive compounds.
First, these collections are intrinsically biased towards known bioactive chemical space that is, the chemical space spanned by known drug molecules and bioactive natural products. Although this is, by definition, a fruitful region for the discovery of biologically useful molecules, it does potentially run the risk of omitting a vast number of bioactive small molecules present in unexplored regions of chemical space from any screening process 1 , Furthermore, it is likely that the low-hanging fruit within the boundaries of known bioactive chemical space have already been picked This is particularly important from a business perspective, with crowded intellectual property space an ever-growing problem Indeed, this is a general disadvantage associated with the use of commercially available compound collections, which are likely to have been thoroughly panned for bioactive constituents.
Such deficiencies in current compound collections are evidenced by the continuing decline in drug-discovery successes Therefore, there is a demand, both from patentability and therapeutic perspectives, for novel biologically active molecules with unusual modes of action that function on underexploited drug targets.
Medicinal chemistry research has traditionally been focused around a limited set of biological targets. Indeed, there are only approximately distinct targets of the current pharmacopoeia 29 , To put this in perspective, the informational content of the human genome has been estimated at around 30, genes 31 , The term 'undruggable' has been coined to describe those biological targets and processes that bear little resemblance to the molecular drug targets exploited in present-day drug therapy and have thus historically been thought of as difficult, if not impossible, to modulate with small molecules 29 , Human genetics and physiology are increasingly revealing the root causes of human disorders, and this has resulted in validation of several new targets for a range of human diseases 34 , However, the majority of the relevant targets and processes fall into the 'undruggable' category 29 , 33 , These include transcription factors, regulatory RNAs, oncogenes and processes such as protein—protein interactions and protein—DNA interactions 29 , It has been argued that one of the reasons why these processes are traditionally viewed to be impervious to modulation by small molecules is because of deficiencies in existing compound collections be they pharmaceutical or commercially available.
That is, the candidate small molecules that populate many screening collections seem to be well suited to modulating 'traditional' medicinal chemistry targets, but lack the necessary structural elements required to modulate other processes 29 , 33 , 34 , 35 , 36 , Thus, although vast numbers of compounds from such libraries are frequently screened at great expense, relatively few biologically active 'hits' against these 'undruggable' targets have been found Therefore, there is a clear need for new small-molecule collections that span regions of bioactive chemical space not accessed by traditional compound libraries in order to identify molecules capable of modulating these more challenging targets vide infra.
The problems associated with the use of natural products and 'traditional' commercially available combinatorial-type libraries in screening experiments have spurred the development of a variety of synthetic approaches for the de novo creation of small-molecule collections 9 , Most of these 'modern' methods have abandoned the mass synthesis and screening dogma underpinning early combinatorial chemistry and instead seek to either 1 identify and efficiently access areas of chemical space that have an enhanced probability of containing bioactive compounds or 2 efficiently interrogate wide regions of chemical space simultaneously 3 , 4 , The former approach is exemplified by methods such as biologically oriented synthesis 38 , biology-inspired synthesis 4 , privileged structure synthesis 39 and diverted-total synthesis 40 , which seek to generate compound libraries based around the core structures of known biologically active molecules, typically natural product templates The rationale behind this approach is that evolutionary pressure has 'prevalidated' natural products, and thus compounds that are structurally similar, to be able to modulate biological systems 3 , 4 , 10 , Consequently, it has been argued that such compound libraries should have a high degree of biological relevance, that is, contain a high proportion of biologically active compounds.
However, such methods have an intrinsic preencoded scaffold bias and inevitably generate compound collections with a relatively low degree of overall scaffold diversity Thus, only a relatively small region of total chemical space is covered, with a heavy emphasis towards known bioactive regions However, what if one wishes to access unexplored regions of chemical space?
These areas may contain molecules with exciting, novel biological properties, which interact with new target molecules or function by means of novel modes of action In particular, there is a demand for compounds with atypical molecular scaffolds. The known universe of organic chemistry is generally dominated by a remarkably small number of molecular scaffolds; for example, in a recent study of known cyclic molecules, 0.
This scenario demonstrates a clear need for novel molecular scaffolds to explore and exploit uncharted regions of chemical space In this context, a less-focused approach is required. The use of non-biased, diversity-driven synthetic approaches, which aim to access a wider range of chemical space by virtue of increased library structural diversity, may thus be more useful It is widely accepted that it is not synthetically feasible to produce all theoretically stable, small carbon-based molecules 3 , 12 , Furthermore, making and screening molecules cost, both in terms of time and money 3 , 9 , Thus, the synthesis of a molecular library that achieves wide coverage of bioactive chemical space presents a formidable challenge to the synthetic chemist; selectivity is an important consideration 3.
The ideal synthesis of a structurally diverse library is one in which this diversity is achieved in the most efficient manner possible 9. DOS seeks to achieve this goal, primarily through the efficient incorporation of multiple molecular scaffolds in the library. DOS has been defined as the deliberate, simultaneous and efficient synthesis of more than one target compound in a diversity-driven approach The overall aim of a DOS is to generate a small-molecule collection with a high degree of structural, and thus functional, diversity that interrogates large areas of chemical space simultaneously.
This includes known bioactive chemical space which, by definition, is a fruitful region for the discovery of biologically active agents and 'un-tapped' regions of chemical space, which may contain molecules with exciting and unusual biological properties that have thus far escaped the attention of humans and perhaps even nature In principle, the screening of such libraries should provide hits against a range of biological targets, including those typically viewed as being more challenging, with increased frequency and decreased cost This should yield novel chemical probes for biological research and new drugs for therapeutic interventions The overall planning strategy of a DOS differs considerably from that used in 'traditional' combinatorial syntheses Fig.
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These metrics are regularly updated to reflect usage leading up to the last few days. Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts. The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric. Find more information on the Altmetric Attention Score and how the score is calculated. A wide range of secondary alkyl and aryl amines and primary and secondary alcohol-derived MTHPs are compatible with the described reaction which, coupled with the enormous diversity of commercially available alcohols and secondary amines, suggests broad applicability of the reaction in fragment-based library design.
Diversity Oriented Synthesis View all 11 Articles. In the interdisciplinary research field of chemical biology and drug discovery, diversity-oriented synthesis DOS has become indispensable in the construction of novel small-molecule libraries rich in skeletal and stereochemical diversity. DOS aims to populate the unexplored chemical space with new potential bioactive molecules via forward synthetic analysis. Since the introduction of this concept by Schreiber, DOS has evolved along with many significant breakthroughs. It is therefore important to understand the key DOS strategies to build molecular diversity with maximized biological relevancy. Small molecules play an indispensable role in the fields of drug discovery and chemical biology due to their unique features compared to biologics, polymers, and nanoparticles Samanen, However, while the knowledge of biological systems has grown in the post-genomic era, the discovery of novel small molecular therapeutics or bioprobes has become more complicated.
Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small.
Metrics details. Despite numerous efforts to eradicate the disease, malaria continues to remain one of the most dangerous infectious diseases plaguing the world. In the absence of any effective vaccines and with emerging drug resistance in the parasite against the majority of anti-malarial drugs, the search for new drugs is urgently needed for effective malaria treatment. The goal of the present study was to examine the compound library, based on indoles generated through diversity-oriented synthesis belonging to four different architecture, i.
Download a PDF copy here. Despite hundreds of years of development, the basic strategy of synthetic organic chemistry - convergent generation of a target molecule from simpler starting materials - has remained largely unchanged. Building upon the goals of combinatorial chemistry a largely failed attempt to address this issue , the emerging method of diversity-oriented synthesis DOS is poised to revolutionize the discovery and development of new pharmaceuticals. Arising from the intersection of chemistry and biology, DOS combines the structural diversity of natural products with the transformative power of synthetic chemistry to rapidly interrogate larger expanses of biologically-active chemical space than ever before possible. Perhaps the most significant contribution from the field of synthetic organic chemistry is the improvement of human healthy through the generation of biologically active compounds and pharmaceuticals.
Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections focused libraries , can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review. Abstract Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target.
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В Севилье есть больницы получше. - Этот полицейский… - Клушар рассердился. - Он уронил меня с мотоцикла, бросил на улице, залитого кровью, как зарезанную свинью. Я еле добрел. - Он не предложил вам больницы поприличнее.
Он решил подумать об этом через минуту. Сейчас ему надо было совершить давно уже откладываемую прогулку в туалетную комнату. ГЛАВА 64 Сьюзан осталась одна в тишине и сумерках Третьего узла.
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ПООБЕДАЕМ У АЛЬФРЕДА. В 8 ВЕЧЕРА. В другом конце комнаты Хейл еле слышно засмеялся.
ГЛАВА 126 - Одна минута. Джабба посмотрел на ВР. Стремительно исчезал уровень авторизации файлов - последняя линия обороны. А у входа толпились бандиты.
И вдруг Сьюзан увидела, что кнопка вызова вовсе не мертва, а просто покрыта слоем черной сажи. Она вдруг начала светиться под кончиком пальца. Электричество .
Человек благоговейно потянулся к закрепленной на брючном ремне батарее: эта машинка, подарок одного из клиентов, подарила ему новую жизнь. Теперь он мог принимать заказы в любой точке мира. Сообщения поступали мгновенно, и их нельзя было отследить. Он торопливо повернул выключатель. Стекла очков блеснули, и его пальцы снова задвигались в воздухе.
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