- Molecular design of high solubility compounds that balances potency and selectivity imposes a challenge in drug discovery.
- Here we present a case study to explore the process of applying single crystal X-ray diffraction and identification of key intramolecular and intermolecular interactions to drug design.
- This work aims to build upon well-established Discovery methods for enriching for solubility and integrate a pharmaceutical strategy that leverages crystallographic determination to enable rational design of soluble preclinical candidates.
Solubility remains a foremost challenge in small molecule drug design and development. Molecular design of high solubility compounds that balances potency and selectivity imposes a challenge in drug discovery. Recent publications provide insight into insolubility in part driven by the interactions involved in stable crystal packing of solid API. Methods for elucidating key interactions in small molecule crystal formation is thus important for the determination of the origin of insolubility and potency, where disruption of crystal packing could be an alternative method for improving aqueous solubility. Crystallographic approaches, however, are often time-intensive, making implementation in drug discovery a challenge. Here we present a case study from Merck aimed to explore the process of applying single crystal X-ray diffraction and identification of key intramolecular and intermolecular interactions to drug design. Crystal structure of the protein-ligand complex was used to determine key interactions driving potency. Solubility and melting point analysis were carried out to understand the origin of poor solubility and molecular match pair (MMP) analysis was used to guide understanding of chemical modifications that might broadly serve as methods for disrupting otherwise strong crystal packing. Further, crystal packing energy and hydration energy were evaluated using a simplified crystal structure prediction workflow. Altogether this work suggests that insight into molecular interactions might guide chemical modifications that favor high solubility and enable rapid generation of a lead molecule.
Tina Xiong, Associate Principal Scientist, Merck
