Major neuropsychiatric and neurological disorders are characterized by dysregulation of glutamatergic neurotransmission. Slowing glutamate uptake with selective sodium-dependent glutamate transporters (EAAT1–5) inhibitors could improve transmission at glutamatergic synapses and provide therapeutic benefit under some conditions. Understanding the precise role of EAAT2 in health and disease requires identification of new selective EAAT2 modulators. In this study, we applied structure-based tools to the discovery of a novel and selective allosteric hEAAT2 inhibitor.

High-throughput screening (HTS) is a powerful strategy in drug discovery to identify chemical starting points for drug discovery and tool compounds for chemical biology, respectively. Although small molecule drug discovery efforts have largely focused on enzymes and GPCRs, there has been an increased desire for identifying small molecules as modulators of protein complexes. Such difficult targets require more sophisticated HTS-compatible binding and activity assays. However, these newer HTS approaches are hampered by generating a large percentage of undesirable hits. Thus, appropriate triaging strategies are required to identify quality hits, and here we discuss such strategies.

The talk will summarize our most recent development efforts to facilitate drug discovery activities targeting KRAS signaling pathway. We have produced the full spectrum of pathway proteins, including wild-type and mutated KRAS, several GEFs, GAP, and kinases. We have established and validated a number of biochemical and biophysical assays for these targets, including the direct inhibition of mutated KRAS activities and RAS-SOS1 interactions. 

Development of small molecules modulating protein-protein interactions can be difficult due to large and shallow interaction interfaces. Antibodies are ideal for targeting PPIs, but they lack cell permeability. Macrocycles occupy an intermediate space between small molecules and antibodies, having sufficient size and functionality to interact specifically and with high affinity with PPI surfaces. Accordingly, mRNA display is a highly valuable technology to identify and optimize peptide-based macrocycles.

DNA-encoded libraries (DELs) are increasingly popular as a source of protein ligands. An important issue moving forward is to develop more structurally diverse and stereochemically complex DELs, particularly with respect to “largish” molecules, such as non-peptidic macrocycles that may be suitable for targeting difficult-to-drug proteins, such as transcription factors. Recent efforts along these lines will be described.

Although the evolution from initial fragment to advanced hit or lead is possible without routine crystallographic support, high-resolution structures of the protein–fragment complex greatly facilitate the process. However, it can be challenging to routinely obtain these crystals. In these instances, NMR spectroscopy is the method of choice to guide the medicinal chemistry campaign. I present case studies of recent NMR structure-based drug design for fragments.

This talk will offer the opportunity to discuss the impact that biophysical methods can have at different stages of the drug discovery process. By presenting case studies taken from the Astex pipeline, the advantages and limitations of applying biophysical techniques, such as NMR, SPR, and X-ray crystallography, to fragment-based drug discovery will be discussed.

A presentation describing the application of flexible approaches to fragment-based lead generation, whereby choice of screening method and fragment sets to test are tailored to the bespoke project needs and target feasibility. Several examples of AstraZeneca projects will be used to illustrate a number of screening strategies and subsequent chemical optimisation from hits to leads.

We present a story about growing a small molecule fragment to an oral drug candidate with in vivo efficacy for a PPI program. We optimized a fragment into undruggable space to learn about the protein target and then used that information and tools generated along the way to guide a second fragment program that focused on efficiency and maintaining drug-like properties for the final drug candidate.

Research of tomorrow is moving towards a more collaborative, open source and platform-independent environment. CDD Vault facilitates more effective research and collaboration by easing the chemical and biological complexity of drug discovery with chemical and batch registration, data visualization and an ELN integrated into a private, secure and collabor vault. 

Modulation of the innate immune receptor, STING, is of pharmacological interest for both oncology and autoimmune indications. Binding of cyclic dinucleotide 2’3’-cGAMP to dimeric STING stabilizes a ‘lid-closed’ protein conformation, ultimately inducing interferon production. Biophysical characterization of different classes of STING ligands using surface plasmon resonance (SPR) has revealed significant differences in binding kinetics, stoichiometry and mode of action. The results of complimentary techniques further support these observed mechanistic differences.

Small-molecule drug discovery can be hindered by aggregating compounds that act as non-selective inhibitors of drug targets. These aggregates appear as false positives in high-throughput screening campaigns and can complicate structure-activity relationships during triage and compound optimization. They can also cause problems in secondary biophysics assays, such as SPR. I’ll discuss high-throughput microplate-based approaches to identify compound aggregation.