Lawton Progress in Medicinal Chemistry

1. Auflage 2014
ISBN: 978-0-444-63395-8
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 53, 216 Seiten

Reihe: Progress in Medicinal Chemistry

Progress in Medicinal Chemistry provides a review of eclectic developments in medicinal chemistry. This volume continues in the serial's tradition of providing an insight into the skills required of the modern medicinal chemist; in particular, the use of an appropriate selection of the wide range of tools now available to solve key scientific problems, including g-secretase modulators, P2X7 antagonists as therapeutic agents for CNS disorders, N-type calcium channel modulators for the treatment of pain, and more. - Extended timely reviews of topics in medicinal chemistry - Targets and technologies relevant to the discovery of tomorrow's drugs - Analyses of successful drug discovery programmes

Autoren/Hrsg.

Lawton, G.

Leseproben

Chapter One Structure-Based Drug Design for G Protein-Coupled Receptors
Miles Congreve; João M. Dias; Fiona H. Marshall    Heptares Therapeutics Ltd, BioPark, Welwyn Garden City, Hertfordshire, United Kingdom Abstract
Our understanding of the structural biology of G protein-coupled receptors has undergone a transformation over the past 5 years. New protein–ligand complexes are described almost monthly in high profile journals. Appreciation of how small molecules and natural ligands bind to their receptors has the potential to impact enormously how medicinal chemists approach this major class of receptor targets. An outline of the key topics in this field and some recent examples of structure- and fragment-based drug design are described. A table is presented with example views of each G protein-coupled receptor for which there is a published X-ray structure, including interactions with small molecule antagonists, partial and full agonists. The possible implications of these new data for drug design are discussed. Keywords GPCR Structure-based drug design SBDD Fragment-based drug design FBDD Fragment Antagonist Agonist 1 Introduction
All cellular surfaces within the human body encompass membrane spanning proteins, which sense the environment and trigger intercellular communication by activating signal transduction pathways. G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and they mediate responses to diverse natural ligands including hormones, neurotransmitters and metabolites, which can vary in structure from simple ions, through small organic molecules to lipids, peptides and proteins [1–3]. Binding of the ligand to the GPCR protein results in a conformational change. This leads to recruitment of intracellular signalling molecules including G proteins and ß-arrestin [4,5]. GPCR activation can lead to rapid cellular responses such as the activation of ion channels, slower responses mediated by cascades of intracellular enzymes or long-term changes in gene expression. Such events can result in various physiological responses including contraction or relaxation of smooth muscle, synaptic transmission in the nervous system, recruitment of immune cells to sites of inflammation or long-term behavioural changes [6]. The prevalence of GPCRs combined with their pivotal role in cell sensing and signalling means that they are one of the richest sources of drug targets for the pharmaceutical industry. Drugs that mimic or block the activity of the natural ligands of GPCRs are used to treat diseases of the central nervous system, such as schizophrenia and Parkinson’s disease, diseases of the cardiovascular and respiratory system, such as hypertension and asthma, metabolic diseases including diabetes and obesity, as well as cancer and HIV infection [7–9]. Currently, up to 30% of marketed drugs are directed at GPCR targets [10,11]. Despite this success, a wealth of novel drug targets remains as yet untapped. Fewer than 20% of the 390 non-olfactory GPCRs have been drugged with small molecules and over 100 of these receptors remain ‘orphans’ whose ligands and biology are as yet uncharacterised [12]. In 2010 there were over 3000 GPCR-targeted drugs in clinical development, although the majority were aimed at the same targets as existing drugs [13]. During the past 5 years there has been a revolution in the industry’s approach to GPCR drug discovery, enabled by the ability to obtain purified protein for biophysical and structural studies. The structures of more than 20 GPCRs have been solved in complex with peptides and small molecule ligands and, in some cases, in both active and inactive conformations. This provides an unprecedented wealth of information regarding the molecular interactions of ligands with their receptors, allowing rational structure-based drug design (SBDD) to be employed effectively with GPCRs for the first time. Here we review the information obtained from GPCR crystal structures with an emphasis on the key interactions within the ligand binding sites and some examples of how this knowledge is starting to be exploited for drug discovery. We also briefly outline complementary approaches to structure-based drug discovery including fragment-based screening. Finally, we discuss future challenges and opportunities in this rapidly moving field. 2 Structural Architecture of GPCRs
GPCRs feature the common topology of seven membrane spanning a-helices (7TM) with an extracellular N-terminus and intracellular C-terminus. Although all GPCRs are considered to be derived from a common ancestral protein they have diverged into a large family with over 800 members which can be classified into different sub-families [14]. Over 400 of these are olfactory receptors involved in smell and taste. The remaining receptors fall into five main families (Class A, Secretin and Adhesion [together Class B], Class C and Frizzled). Class A or rhodopsin is the largest family with approximately 300 members and includes the aminergic (e.g. dopamine and histamine) receptors, neuropeptide receptors, chemokine receptors, receptors for lipids and eicosanoids and glycoprotein hormone receptors. Despite the great diversity in ligand structure, the mechanisms involved in receptor activation are remarkably well conserved, with almost all drugs for Class A receptors binding to the same region, whatever the nature of the natural endogenous ligand [15]. Class B GPCRs comprise both the Secretin family (15 members) and the Adhesion family (33 members). The Secretin family includes many targets important in disease including the glucagon-like peptide receptor (GLP-1), a target for diabetes, and the parathyroid hormone receptor (PTH1), a target for bone diseases such as osteoporosis. This family has proved extremely difficult to drug with small molecules, although many of the natural peptide ligands serve as therapeutic agents [15,16]. Structures of the first two representatives of Class B receptors, the glucagon receptor and the corticotropin releasing factor (CRF1) receptor have recently been solved [17,18] (Table 1.1). The Adhesion family members are characterised by a conserved transmembrane domain (TMD) linked to a very large extracellular domain, which comprises adhesion-like subdomains and a domain that undergoes intracellular proteolytic cleavage (known as the GPCR proteolytic site or GPS domain) to yield two non-covalently attached subunits [43]. Currently, most Adhesion receptors are orphans and their biology and signalling are not well understood. Several have been reported to be activated by interactions with extracellular matrix proteins. Table 1.1 List of Published GPCR Crystal Structures The figures in this table were prepared with the software Pymol [42]. Class C GPCRs, which include the glutamate receptor family, also have a large N-terminus with a bi-lobed amino acid binding domain known as the ‘Venus fly trap’. The receptors function as dimers and bind simple amino acids such as glutamate and ?-aminobutyric acid (GABA) as well as ions [44]. Three taste receptors also fall into this family, including those for sucrose, aspartame and umami. Only two members of Class C are the target of marketed drugs (the GABAB receptor and calcium sensing receptor), however there are many drugs directed at glutamate receptors currently in development [45–47]. Drugs for this family of GPCRs can bind either within the extracellular amino acid binding domain or within the TMD, where they act as allosteric modulators of the endogenous ligands. Lastly, the Frizzled Class of GPCRs includes 10 Frizzled (FZD) receptors and the smoothened receptor (SMO). FZD receptors bind Wnt glycoproteins whereas SMO is activated by formation of a complex with another membrane protein called patched [48]. The TMD of this family is linked to a large extracellular domain containing a cysteine rich region that binds the Wnt ligands. In 2012 the first small molecule drug targeting this family was approved for the treatment of cancer, vismodegib. This compound binds within the TMD of SMO [49]. Recently, the structure of the SMO receptor in complex with a small molecule ligand has been solved (see Table 1.1) [41]. 3 GPCR Protein–Ligand X-Ray Structures
The difficulty in obtaining diffracting crystals for GPCRs is due to the inherent flexibility of these receptors, for they exist in multiple conformational states. Crystallisation requires that the protein be in a single, homogenous conformation, which can be obtained at least to some extent by the addition of a ligand that preferentially binds to a single conformation (e.g. antagonist or agonist). Crystallisation of membrane-associated proteins is conducted in a detergent medium. During crystallisation, crystal contacts are formed between hydrophilic regions of the protein that protrude from the detergent micelles. So as well as...