The application of rational drug design is considered to be more efficient and prosperous than the traditionally slow and laborious way of drug discovery since it aims to understand the molecular basis of a disease. Rational drug design necessitates a broad collaboration of many disciplines for the development of novel drugs with optimum pharmacological profile. Theoretical chemists, biologists, medicinal chemists, doctors, pharmacists specialized in pharmacokinetics and drug capsulation must develop collaborative research networks in order to succeed in controlling a target disease. A major component of the rational drug design is the application of the experimental method of X-ray crystallography. This powerful technique is essential for the interpretation of the function and properties of biological molecules. An additional component of the rational drug design is the application of the theoretical methods that can provide quantitative descriptions of the physical and chemical properties of molecular structures, the molecular interactions and the thermodynamics of association.
DRUGDESI aim was to recruit an experienced researcher in computational calculations to complement the Structural Biology and Chemistry Group activities focusing mainly on biochemical and structural studies at the time. Efforts were directed towards extracting valuable information from the experimental data obtained using X-ray crystallography for the design of improved inhibitors of glycogenolysis, potential hypoglycaemic agents.
Dr. Joseph M. Hayes, a More Experienced Researcher (MER), was employed for this purpose and successfully fulfilled the objectives of the project by setting up in silico calculations in our group and sharing his knowledge with members of both our group and IOPC and especially with young scientists in the frame of their MSc theses. This work has already resulted in 8 publications in peer-reviewed journals and 3 manuscripts in preparation. During his work, two of the most potent glycogen phosphorylase inhibitors identified to date with experimental inhibition constants (Ki values) of 116 and 270 nm. Their identification was largely driven by computation and predictions for even more potent analogues of these leads are still currently under synthesis (in collaboration with Prof. Gimisis, Univ. of Athens, Greece, and Prof. Praly, Univ. Claude Bernard Lyon 1, France).
In summary, the benefits of this Marie Curie ToK action for both the MER and our group are listed below: