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- Volume 11, Issue 7, 2011
Current Topics in Medicinal Chemistry - Volume 11, Issue 7, 2011
Volume 11, Issue 7, 2011
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Editorial [Hot topic: Effect of Stereochemistry in Medicinal Chemistry and Drug Discovery (Guest Editor: Simona Rapposelli)]
More LessAlthough in 1986 E.J. Ariens wrote “Stereochemistry: a source of problems in medicinal chemistry”, chirality dominates in nature, in biological systems (i.e. aminoacids, receptors, enzymes) and in disposition and metabolic processes in which receptors and enzymes are involved. The complexity of biological systems, together with the different pharmacological and pharmacokinetic properties of enantiomers prompt medicinal chemists to take advantage in new asymmetric synthesis and in separation technologies. Beyond the groundbreaking strategies of drug design in which efficacy and safety should be hold imperative, the development of dynamic theoretical models, which taking account the stereoselectivity and the asymmetry of the target, emerged as needful tools to improve pharmacological therapies. Despite the true difficulty to develop new chiral drugs or new molecules with elevate stereoselectivity, chirality keep affecting both the modern pharmaceutical industry and drug discovery. Stereochemistry represents a challenge to improve the activity and/or to reduce toxicity of drugs throughout the rise of new theoretical and synthetic strategies. This issue offers an useful overview and entry point into the discussion of stereochemistry and its consequences for drug development. The review paper of Daniel Kenyon et al. gives a very detailed and highly informative description of the regulatory guidelines regarding chirality of drugs and the changes in drug development resulting from these. Moreover, this paper includes an examination of some of the practical concerns of stereochemistry in drug discovery campaigns highlighting the need to address chirality in the early of drug discovery process. The review of Subhash Basak et al is an overview of some theoretical methods useful to assess the importance of chirality in behaviour of molecules useful in pharmacology, agrochemistry and environmental toxicology. In particular, this paper detailed analyses different mathematical models to predict the properties of chiral drugs throughout the numerical characterization of chiral compounds. This issue carries on with the effects of stereoselectivity and the role played by chiral centers in the interaction with different biological targets such as enzymes (i.e. kinase inhibitors), and nuclear receptors (i.e. PPAR, VDR). The clinical importance of stereochemistry has been clearly discussed in other two reviews that provide hope in the fight against tubercolosis and cancer, two globally health problems, not yet overcome. The Sessel & Fernandez manuscript outlines the need for the combined use of computational methods, biomolecular structure and bioinformatics in rationally drug design. Biomolecular structure and bioinformatics are described as essential instruments to design novel drugs with increased selectivity. The application proposed by Sessel & Fernandez in the field of drug specificity is on modelling molecular filters to specifically target kinases with cancer-related mutations. The review article by Thomas Craig et al. talks about the key role played by stereochemistry in the interaction with several pharmacological targets, and in particular with kinases which are involved in the cellular signalling pathway. This paper discusses the effects induced by the introduction of chiral centers in terms of potency and selectivity of new small kinase inhibitors The review article by Kozikowski et al. summarizes the importance of stereochemistry in anti-TB drug activity and in the discovery and development of anti-TB drug candidates. The authors focus on the advantages in potency, efficacy and selectivity obtained by the development of single enantiomers of chiral drugs in the discovery of novel anti-TB agents . The review article by Fulvio Loiodice et al. is a detailed discussion of the influence of stereochemistry on PPAR activation, focusing on the PPAR binding mode and how chirality affects it. To better explain and comprehend the PPAR stereoselectivity, the authors suggest the application of cristallization methods together with the analysis of the complexes formed by PPAR and their ligands. The differences between several ligands targeted PPAR as well as the pharmacophore and the role played by the stereogenic centers in the PPAR-ligand complexes are discussed. The review article by Chiellini & De Luca focuses on the stereochemistry aspect on vitamin D analogs and their interaction with VDR (Vitamin D Receptor). In particular, this paper outlines the main structural modifications of vitamin D skeleton as the main tool to elucidate the role played by aminoacids within the binding pocket to anchor the ligands. The strategy reported here is based on the understanding of the structure activity relationship of vitamin D analogs which represent one of the most important resource for researchers in this field. The review of Taliani et al. summarises the structural requirements needed to obtain TSPO ligands with high affinity and selectivity. Because of the lack of crystallographic data due to the difficulty of isolate this receptor, this paper elucidate the structural requirements on the basis of a detailed analysis of the SAR of TSPO ligands designed and tested. The review of Rasmus et al focuses on the stereochemical and conformational aspects related to the activity of glutamate receptors. Both the stereochemical and the conformational considerations were reported on the basis of biostructural knowledges of the agonist binding pockets based on structure-activity relationship of ionotropic glutamate receptors. This review highlights the influence of stereochemistry in the ligand fitting with the receptor as well as in the conformational space of the ligand. I would like to thank all the authors for their excellent contributions and participation in this issue and all the Referees who contributed to improve the quality of the whole issue. I am also grateful to the editor-in-chief, Dr. Allen Reitz, for the invitation and the opportunity to arrange this special issue as guest editor. Taking into account the ever growing needs for new and more efficacious drugs and the evident existence of a high degree of stereoselectivity within the complexity of the targeted biological system, I hope this issue will provide useful tools to pursue and develop new and more specific strategies for satisfing the prime demands of the pharmacological therapy: the safety and the efficacy. This issue may represent an useful guide for the medicinal chemistry research community and other related fields in the future.
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The Significance of Chirality in Drug Design and Development
Authors: W. H. Brooks, W. C. Guida and K. G. DanielProteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a “coin toss” as to whether or not the “ideal” chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.
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Numerical Descriptors for the Characterization of Chiral Compounds and their Applications in Modeling Biological and Toxicological Activities
Authors: Ramanathan Natarajan and Subhash C. BasakDue to the advancement in chiral synthesis and separation technology and the new regulatory policies for chiral pharmaceuticals several manufacturers are replacing the previously marketed racemate chemicals with single enantiomeric products, the so called chiral switch. Though 25% of agrochemicals are chiral in nature, most of them are sold as racemates or enantiomer enriched products. Chiral pesticides and some of the pharmaceuticals reach the human food chain as pollutants. Stereoisomers (enantiomers and diastereoisomers) not only differ from one another in their medicinal effects, but also in their phramacokinectic (adsorption, distribution, biotransformation and excretion) profiles and toxicological properties. Several recent attempts have been reported in the literature on developing mathematical models to predict the properties of chiral molecules from structure and such methods utilized numerical characterization. A comparison of different mathematical approaches on the numerical characterization of molecules with chiral center(s) and a brief background on the importance of stereochemistry in pharmacology, agrochemistry and environmental toxicology is presented.
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Selectivity Filters to Edit Out Deleterious Side Effects in Kinase Inhibitors
Authors: Sean Sessel and Ariel FernandezAs the molecular etiology of cancer unravels, revealing the heterogeneous nature of the malignancy, multitarget drug treatments are more frequently advocated. Such therapeutic avenues often target kinases, the basic signal transducers in the cell. Because kinases share common evolutionary backgrounds, they also share many structural attributes, making it difficult for molecular targeted therapy to distinguish between paralogs. Thus, kinase inhibitors (KIs) tend to have undesired cross-reactivities, resulting in potentially lethal side effects. The health risks are obviously higher in these multi-pronged treatments when contrasted with the effects of more selective therapeutic agents. Using a nonconserved physicochemical biomarker, we present a rationally designed molecular filter that enables the control of specificity and the development of adjuvant drugs to edit out the side effects of the primary therapeutic agent. These editors work by overlapping therapeutically with the primary drug in cancer cells, while interfering with toxicity-related signaling pathways recruited by the primary drug in off-target cells. We then examine the possible application of these filtering methods to specifically target kinases when they present idiosyncratic cancer-related mutations. Such applications open the door to engineer personalized drugs tailored to the genetic makeup of the patient. These various methods of enhancing efficacy and safety show some degree of modularity, allowing drug designers to utilize multiple techniques and various drug combinations to create the safest and most powerful treatment for any given therapeutic scenario.
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Chiral Kinase Inhibitors
Authors: Jian-kang Jiang, Min Shen, Craig J. Thomas and Mathew B. BoxerSmall molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number of asymmetric compounds show great utility as tools for probing kinase-associated biomolecular events as well as promising therapeutic leads. The mechanism by which chirality is introduced varies but includes screening of chiral libraries, incorporation of chiral centers during optimization efforts and the rational installation of a chiral moiety as guided by structural and modeling efforts. Here we discuss several advanced chiral small molecule kinase inhibitors where stereochemistry plays an important role in terms of potency and selectivity.
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Stereochemistry at the Forefront in the Design and Discovery of Novel Anti-tuberculosis Agents
Authors: Qingqing Huang, Rong He and Alan P. KozikowskiToday, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.
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Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods
Authors: F. Loiodice and G. PochettiPeroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated transcription factors that govern lipid and glucose homeostasis playing a central role in cardiovascular disease, obesity, and diabetes. These receptors show a high degree of stereoselectivity towards several classes of drugs. This review provides an overview of most papers reporting the influence of stereochemistry on PPAR activation. Some cases in which chirality is a crucial point in determining the PPAR binding mode are reviewed and discussed with the aim to show how enantiomeric recognition originates at the molecular level. The structural characterization by crystallographic methods of complexes formed by PPARs with their ligands turns out to be an essential tool to explain receptor stereoselectivity.
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The Importance of Stereochemistry on the Actions of Vitamin D
Authors: G. Chiellini and H. F. DeLucaThe seco-steroid hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is the most potent natural metabolite of vitamin D3 and regulates primarily calcium and phosphate homeostasis, but also as a regulator of specific differentiation and of the immune system. Most, if not all, of the biological actions of 1α,25(OH)2D3 are mediated through its specific receptor, the vitamin D receptor (VDR), which is a member of the nuclear receptor superfamily acting as a liganddependent transcription factor with coactivators. 1α,25(OH)2D3 has significant therapeutic potential in the treatment of osteoporosis, rickets, secondary hyperparathyroidism, psoriasis, and renal osteodystrophy. However, the use of 1α,25(OH)2D3 itself is limited because it induces significant hypercalcemia. Vitamin D is a highly flexible molecule and a very large number of analogs have been synthesized by industry and academia in an attempt to provide beneficial therapeutic agents with low calcemic activity. Chemical modifications of every portion of the vitamin D3 molecule (the A, C, and D rings, the 17β-aliphatic side chain, and the 5,6,7,8-diene moiety) have been reported, with the most of the interesting analogs resulting from a combination of several modifications. The three-dimensional structure of both rat and human VDR-LBD have provided significant information for our understanding of the structure-function relationship (SFR) of vitamin D and some synthetic analogs. In this review, we focus on the current understanding of the relationship between selected stereochemical modifications of key structural components (i.e. A-ring, CD-ring and Side-chain) of the 1α,25(OH)2D3 molecule and their effect on biological potency and selectivity. Based on current information, suggestions for the structure-based design of therapeutically valuable vitamin D analogs will conclude the review.
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Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands
Authors: Sabrina Taliani, Isabella Pugliesi and Federico Da SettimoThe (18 kDa) Translocator Protein (TSPO) was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named “Peripheral-type benzodiazepine receptor (PBR)”. It is an evolutionarily wellconserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity.
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Glutamate Receptor Agonists: Stereochemical Aspects
More LessThe neurotransmitter (S)-glutamate [(S)-Glu] is responsible for most of the excitatory neurotransmission in the central nervous system. The effect of (S)-Glu is mediated by both ionotropic and metabotropic receptors. Glutamate receptor agonists are generally α-amino acids with one or more stereogenic centers due to strict requirements in the agonist binding pocket of the activated state of the receptor. By contrast, there are many examples of achiral competitive antagonists. The present review addresses how stereochemistry affects the activity of glutamate receptor ligands. The review focuses mainly on agonists and discusses stereochemical and conformational considerations as well as biostructural knowledge of the agonist binding pockets, which is useful in the design of glutamate receptor agonists. Examples are chosen to demonstrate how stereochemistry not only determines how the agonist binding pocket is filled, but also how it affects the conformational space of the ligand and in this way restricts the recognition of various glutamate receptors, ultimately leading to selectivity.
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Volumes & issues
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Volume 25 (2025)
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Volume (2025)
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Volume 24 (2024)
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Volume 23 (2023)
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Volume 22 (2022)
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Volume 21 (2021)
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Volume 20 (2020)
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Volume 19 (2019)
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Volume 18 (2018)
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Volume 17 (2017)
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Volume 16 (2016)
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Volume 15 (2015)
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Volume 14 (2014)
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Volume 13 (2013)
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Volume 12 (2012)
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Volume 11 (2011)
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Volume 10 (2010)
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Volume 9 (2009)
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Volume 8 (2008)
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Volume 7 (2007)
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Volume 6 (2006)
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Volume 5 (2005)
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Volume 4 (2004)
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Volume 3 (2003)
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Volume 2 (2002)
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Volume 1 (2001)
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