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The initial publications on lead-like properties suggested that small, simple molecules would have higher hit rates and lower affinities than the typical larger, more complex molecules used in classic high-throughput screening (HTS) discovery programs. This concept has now been demonstrated by SGX Pharmaceuticals 49 , who reported typical fragment screening hit rates of 15 for several different target classes. Such high hit rates suggest that it is not necessary to rely on previously known...

Bivalency in the Immune System

IgG and IgE antibodies, prime components of the immune system, are bivalent proteins containing two identical receptors (Fab sites Fig. 2.12) 21 . When binding bivalently to a surface (Fig. 2.12a) or to a soluble bivalent ligand (Fig. 2.12b), we postulate that the enhancement (P) for a given antibody is inversely proportional to the monovalent dissociation constant (K fflnlty) and directly proportional to the effective concentration (Ceff) of ligand near an available receptor (Fig. 2.12). If we...

Discovery of Highly Potent AChE by In Situ Click Chemistry

The target-guided click chemistry approach was first tested with acetylcholine esterase (AChE) (Fig. 15.4). The enzyme plays a key role in neurotransmitter hydrolysis in the central and peripheral nervous system 55, 56 . It has two separate binding sites on either end of a narrow gorge 57 . For fragment assembly by the 326 15 Click Chemistry for Drug Discovery Step 1. Identification of Anchor Molecule 326 15 Click Chemistry for Drug Discovery Step 1. Identification of Anchor Molecule enzyme,...

Protein Tyrosine Phosphatase 1B Finding Fragments in a Fragile Narrow Site

TS offered an accessible, hardy active site. To see whether Tethering could work for more difficult sites, we turned to protein tyrosine phosphatase 1B (PTP1B). The enzyme PTP1B, a key regulator of metabolism, dephosphorylates the insulin receptor, in effect turning it off. Thus, the protein is a key drug target for both diabetes and obesity 13 . However, the enzyme has evolved to recognize phospho-tyrosine, a highly negatively charged moiety for which there are very few drug-like isosteres. We...

SAR by NMR

SAR by NMR was reported in 1996 by Shuker, Hajduk, Meadows, and Fesik 1 as a fragment assembly approach to inhibitor design, using NMR as a structural guide. It is essentially a five-step method 75 that involves screening for weak- binding fragments in two binding sites. In step 1, NMR is used to screen for a weak binding ligand in a first site. In step 2, the ligand is optimized for higher affinity, using NMR structural assays to ensure that binding mode is retained. In step 3, the protein is...

Spleen Tyrosine Kinase Case Study

Spleen tyrosine kinase Syk is a non-receptor tyrosine kinase required for signaling from immunoreceptors in hematopoietic cells. Syk is an inflammatory disease target that controls degranulation of mast cells in asthma 48, 49 . The crystal structure of Syk was obtained by SGX at 2.5 A resolution 50 in the context of our human protein kinase pipeline. While initial crystal forms of Syk were undergoing optimization for crystallographic fragment screening, it was noted that the active site of Syk...

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Initial Leads

Extensive HTS screening of PTP1B using conventional methods did not provide any viable leads. The screening results and subsequent enzymatic analysis revealed the presence of several small isoquinoline diol compounds 160 Da that appeared to be inhibitors of PTP1B at the low micromolar level. Repeated experiments using soaking and co-crystallization protocols failed to show the presence of any of this class of compounds in the active site. In contrast, the active site resi dues appeared to be in...

NMR Screening Using WaterLOGSY

We screened our Drug Fragment Library, Focused Kinase Library and Privileged Fragment Library against a variety of targets including different kinases and a serine protease, using the Water-LOGSY method. Where possible, we set up the experiments in a competition format in which an initial screen for fragment binding was followed by a displacement step with a known tight binder to discriminate fragments binding at the protein active site from nonspecific binders. In order to identify these...

Introduction

Structural biology is an integral part of the drug discovery process in the pharmaceutical industry. Two complementary methods dominate among the experimental techniques capable of providing detailed three-dimensional 3D structural information of therapeutically relevant targets, most often with bound ligands protein crystallography and solution-phase NMR spectroscopy. The structural information these techniques provide continues to grow in depth and breadth, impacting every step of drug...