The EU-funded ‘Enzyme design of medical interest
) project worked on designing
three enzymes for application in biotechnology, biomedicine and industrial processes. Researchers used a previously developed inside-out methodology combining computational protein design
with directed evolution
(DE) to design novel enzymes.
Novel quantum mechanical
) and density-functional theory
strategies were applied to optimise enzyme designs through simulations.Researchers developed a transaminase enzyme to produce the type 2 anti-diabetes drug called sitagliptin
using the inside-out protocol. However, there were several problems with the computational designs and the protocol proved unsuccessful
Following this, researchers worked on designing new enzyme variants to produce a cholesterol-lowering active ingredient called lovastatin acid. These enzymes produced through DE were computationally evaluated using the Anton supercomputer and MD simulations. Analysis revealed that enzymes produced by DE were more effective than computationally designed ones due to a better pre-organisation of the enzyme’s polar environment.
MEDENZYMEDESIGN scientists worked on redesigning natural NADP-dependent enzymes to produce glucose-6-phosphate dehydrogenase activity and to reduce drug-induced oxidative stress for G6PD deficient patients. MD simulations were performed to understand differences in catalytic activity and reaction kinetics of enzymes and their variants.
Project activities have laid the foundation for future research endeavours to improve computational protocols for biocatalyst design. This should facilitate the commercial application of biocatalysts for sustainable industrial-scale production of important chemicals. Targets include diabetes, Alzheimer’s, Parkinson’s and Huntington’s diseases.