I am a PhD student on an industrial studentship sponsored by Janssen. My project involves using computational methods in the design of covalent inhibitor compounds. Covalent inhibitors are distinct from conventional reversible inhibitors as they ‘permanently’ bind to their target through the formation of a covalent bond. There are numerous advantages to designing drugs with a covalent mechanism of action such as increased potency, and the requirement for lower drug dosages. However, there are several safety concerns surrounding covalent drugs as their intrinsic reactivity means they can react indiscriminately with off target proteins. This means careful design of such compounds is necessary to mitigate these concerns, and computational methods have the potential to become essential tools in the design of covalent compounds.
Prior to starting my PhD I completed an MSci project (also in the Mulholland Group), where I used a range of computational methods to investigate the reactivity and stereo-specificity of an aldolase biocatalyst, N-acetylneuraminic acid lyase (NAL). Interestingly, the crystal structure of the E192N variant of NAL showed two distinct binding modes of the substrate in the active site, and it had been proposed that these different binding modes resulted in the observed stereo-selectivity of this enzyme. I used a combination of classical molecular dynamics simulations, binding affinity calculations and combined QM/MM reaction simulations to investigate the selectivity and activity of this enzyme.