INPhINIT Incoming Fellowship – Dissection of molecular mechanisms of carbohydrate-active enzymes involved in disease using computer simulation
The main objective of the project is the rational design of inhibitors for enzymes involved in Gaucher and Fabry diseases. The enzymes β-glucosyltransferase and a-galactosyltransferase, responsible of the synthesis of the carbohydrates that accumulate in these diseases, will be explored by means of quantum mechanics/molecular mechanics (QM/MM) simulations, in which the group has a large and successful experience. The electronic and structural properties of the transition state (TS) of the reaction will be analyzed and small molecule inhibitors will be proposed that match these properties and their degree of TS mimicry will be optimized. These investigations will be extended to glycoside hydrolase enzymes directly responsible for Gaucher and Fabry syndromes (glucocerebrosidase and α-galactosidase, respectively), in order to design chemical probes for disease diagnosis. The work will be done in collaboration with an international team of structural biologists from the University of York (G. J. Davies) and chemical biologists from the University of Leiden (H. S. Overkleeft), with whom the group has established a fruitful collaboration. Computer resources will be provided by the Institute of Theoretical and Computational Chemistry (in house research cluster) and the Barcelona Supercomputing Center.
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