Drug Discovery

Background and Context

Small molecules offer a vast space for molecular design. Pharmaceutical chemistry tries to either construct new small molecules for the treatment of human disease or to identify new pharmacological roles of known small molecules. Most often these molecules target proteins by binding to important sites on these much larger and flexible objects. This binding can interfere with the normal function provided by the protein in humans, which can have both beneficial and deleterious effects. Successful drug molecules need to interact with the protein or class of proteins they target in the live organism. Cross-activities lead to side effects and target specificity is an important consideration in drug development. Drug molecules also need to get to the relevant tissues and later be degraded and/or excreted safely.

Our Approach

We use a set of computational in-house tools to find novel pharmaceutical functions of existing small molecules or fragments thereof. Our tool for in silico screening of fragments is SEED, a software using an efficient (1 second per fragment) approximation of the Poisson equation to calculate the electrostatic contribution to the free energy of binding in a fully rigid approximation (see Software Downloads). A second area of current emphasis is a virtual coupling tool (AutoCouple) to exploit feasible synthesis pathways. This tool is designed to foster the collaboration with Prof. Cristina Nevado's group at the University of Zurich who are experts in organic synthesis. Together, we try to optimize the pharmaceutically relevant properties of candidate molecules. Using the strategies outlined above, we have developed a number of highly active compounds targeting proteins important for the growth of malignant tumors. These include kinases, bromodomains, and epitranscriptomics targets.