Associate Principal Scientist Merck Boston, Massachusetts
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. Here we present a case study that aims 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 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.
Learning Objectives:
Participant will be able to describe the role of crystallinity, ionization potential, and lipophilicity on solubility design and the relation to general solubility equation, and computationally-derived sublimation and hydration energy.
Participant will be able to conduct studies to inform on lipophilicity and structure- solubility relationship, including, in relation to 3-D structure via crystallography and 2-D structure via molecular match pair.
Participant will be able to list methods of crystal structure determination, and gain structure-informed insight to molecular design, including single crystal XRD, crystal structure prediction, and polymorphism considerations.
