Developing Electron Microscopy as a Tool in Structure-Based Drug Design (360G-Wellcome-109158_B_15_A)

Structure-based drug design has relied heavily upon X-ray crystallography to yield atomic resolution structures of protein targets, subsequently used for inhibitor design. However, the structures obtained are in a static state which may not be a true representation of how the protein exists under physiological conditions. The advances in Electron Microscopy (EM) has led to an increase in the number of near-atomic resolution structures solved and enabled conformational information to be obtained for dynamic systems. Therefore, the project’s ultimate goal is to use EM structures to aid the design of novel therapeutic agents against two different proteins which could be used to treat toxoplasmosis; vacuolar ATPase (V-ATPase) and cytochrome bc1 complex. In silico drug design, including virtual high throughput screening (vHTS) and de novo design, will be conducted to produce putative inhibitors. The compounds will be designed against the most populated functional state of the protein and will be synthesised and screened for their biological activity using in-cell and enzymatic assays. EM can then be used to probe the mode of inhibitor binding to the complex leading to one of the first examples of EM structures being used as a tool in drug discovery.