title: Static and dynamic interactions between GALK enzyme and known inhibitors: guidelines to design new drugs for galactosemic patients.
abstract: The search for inhibitors of galactokinase (GALK) enzyme is interesting for their possible therapeutic application capable to alleviate symptoms in people with classic galactosemia. Several high-throughput screenings in the past have found candidate ligands showing a moderate affinity for GALK. Computational analysis of the binding mode of these compounds in comparison to their target protein has been performed only on crystallographic static structures, therefore missing the evolution of the complex during time. In this work, we applied static and dynamics simulations to analyze the interactions between GALK and its potential inhibitors, while taking into account the temporal evolution of the complexes. The collected data allowed us to identify the most important and persistent anchoring points of the known active site and of the newly identified secondary cavity. These data will be of use to increase the specificity and the affinity of a new generation of GALK inhibitors.
authors.affiliation: Institute of Biomedical Technologies, Italian National Research Council, Via F.lli Cervi 93, 20090 Segrate, MI, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Chiappori
authors.forename: Ivan
authors.initials: I
authors.lastname: Merelli
authors.forename: Luciano
authors.initials: L
authors.lastname: Milanesi
authors.forename: Anna
authors.initials: A
authors.lastname: Marabotti
mesh_terms: D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005686:Galactokinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D005690:Galactose / Q000737:chemistry / Q000378:metabolism; D005693:Galactosemias / Q000201:enzymology* / Q000517:prevention & control; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D005686:Galactokinase; D005690:Galactose