G protein-coupled receptors (GPCRs) are intensely studied as drug targets and for their role in signaling. The rapidly increasing number of atomic resolution crystal structures of GPCRs has revealed how the same protein fold can recognize signaling molecules ranging from small-molecules to peptides and proteins. These breakthroughs provide opportunities to explore structure-based approaches to design ligands of therapeutic targets from diverse receptor families. Lead discovery by library screening relies on two strategies based on fundamentally different philosophies. High-throughput screening (HTS) has been widely used to identify starting points for drug development. However, screening campaigns of large chemical libraries with up to millions of drug-sized compounds often result in low hit rates. Fragment-based drug discovery (FBDD) has emerged as a promising alternative to HTS. FBDD relies on the idea that hit rates from libraries with low molecular weight compounds (&lt; 250 Da) will be higher than those from the drug-like compound sets due to better coverage of chemical space and reduced probability of steric mismatches with the binding site. However, ligands discovered using fragment screening will have weak affinity and need to be optimized to reach activities necessary for biological effects. I will present comparisons of structure-based virtual screening of fragment and drug-like chemical libraries for ligands of adenosine, dopamine, and neurotensin receptors and strategies for designing compounds with tailored selectivity and signaling properties.<br/>

Structure-based screening for GPCR ligands from fragment and lead-like chemical space

255th National Meeting (2018)

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