In recent years, synthetic macrocycles are increasingly considered as a source of drugs. Macrocyle drugs present several attractive features. For example, they can impart exquisite potency and selectivity, especially with challenging Protein-Protein Interactions (PPIs) targets. Additionally, macrocycles often retain optimal physico-chemical properties, such as good solubility and permeability, despite high molecular weight or lipophilicity. A distinctive feature of macrocycles is greater conformational restriction due to fewer rotatable bonds. As a consequence, the ability to accurately and robustly predict free as well as bioactive conformations are key steps in structure-based macrocycle design. Unfortunately, computational conformational analyses often fail to predict global minimum energy states of free ligands. Despite the availability of bioactive conformations from protein-ligand x-ray crystallography, optimization of macrocycles potency can still be an empirical process.  Moreover, conventional metrics to design oral bioavailability for small molecule drugs, such as of Lipinski's 'Rule of Five', are of little use in macrocycle physical chemistry optimization. We will show, with examples from AstraZeneca oncology discovery projects, how measurement by NMR spectroscopy of the conformational landscape of free macrocycles in solution can aid and focus drug design hypotheses, leading to accurate predictions of affinity and physical chemistry properties.

NMR conformational signatures guide the design of macrocycle drug cell activity and permeability: AstraZeneca case studies

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.