Physical chemical properties beyond small molecules: Predictive chemistry for novel drug formulations

Novel pharmaceutical formulations go beyond the classical picture of small biological active molecules delivered in form of tablets, injections, or aerosols. New drug formulations often contain more complex molecules and delivery systems. Some of the latest Covid vaccines have provided contemporary examples of novel of mRNA-based active compounds delivered inside liquid nanoparticle (LNP) formulations.

In general, RNA or DNA-based pharmaceuticals, antibodies, or combined formulations are currently developed at elevated speed for many disease applications. Often carrying a substantial advantage for both target

ing and specific activity against their targets, these formulations also come with completely new challenges in chemical synthesis and production, often based on their very different chemical physical properties. Therefore, a fundamental understanding of the physical and chemical properties of such newly developed formulations is urgently needed. Being able to predict such properties in advance will have a have a critical impact on drug discovery and development efforts.

This project will focus on investigating fundamental physicochemical properties of oligonucleotide-based formulations via computational chemistry. Polyions like oligonucleotides pose distinct challenges in drug development and delivery, not least due to their interactions with solvents, counter-ions, additives, and self-interactions (inter- and intra-molecular), influencing their physical properties.

One such property is the viscosity profile of these systems, which differ significantly from other pharmaceutical formulations, and are currently unpredictable based on a lack of mechanistic understanding of the physicochemical properties of the systems. This poses an unknown risk to the drug development process and usually needs to be investigated intensively at high costs for the projects.

In this project molecular simulation protocols will be developed that investigate the physicochemical properties of model oligonucleotide formulations with the aims of deciphering the underlying reasons driving their properties profiles, and using the predictive power of simulations for the future design of formulations with desired properties.