Scott Lab goal: determine how different human cytochrome P450 enzymes bind and metabolize small molecules
• 25% of human P450 enzymes metabolize drugs, toxins, and carcinogens as a critical first step in their clearance. These P450 enzymes each bind many different substrates, often in multiple orientations, producing multiple products. Regardless of the disease state, the Scott Lab interest is in optimizing metabolism to maintain therapeutic levels and decrease adverse events.
• 50% of human P450 enzymes play key roles in normal human physiology by generating steroid hormones and bile acids, vitamins, fatty acids, and eicosanoids. These P450s are frequently drug targets for various disease states. For these enzymes the Scott Lab focus is enabling novel structure-based drug design.
Methods employed include X-ray crystallography, enzymology, spectroscopy, HPLC, LC-MS/MS, high-throughput screening, NMR
Selected accomplishments
- First structure of steroidogenic CYP17A1 showing how it is inhibited by abiraterone/Zytiga to treat prostate cancer and improvements on this molecule to decrease side effects due to concomitant CYP21A2 inhibition
- First structure of CYP8B1 (involved in bile acid synthesis) is useful for designing inhibitors useful in treating type 2 diabetes and metabolic dysfunction-associated steatotic liver disease, a chronic liver disease affecting 30% of the world’s population.
- Structure of the fetal-specific CYP3A7 with its steroidal substrate DHEA-sulphate, involved in both production of pregnancy-sustaining steroids and drug metabolism
- Solution NMR and enzymology to assess the effects of redox partner protein interaction with P450 enzymes