title: Development and validation of a docking-based virtual screening platform for the identification of new lactate dehydrogenase inhibitors.
abstract: The human muscle isoform of lactate dehydrogenase (hLDH5) is one of the key enzymes of the glycolytic process. It is overexpressed in metastatic cancer cells and is linked to the vitality of tumors in hypoxic conditions. With the aim of identifying new hLDH5 inhibitors, a fully automated docking-based virtual screening platform was developed by considering different protein conformations and the consensus docking strategy. In order to verify the reliability of the reported platform, a small database of about 10,000 compounds was filtered by using this method, and the top-ranked compounds were tested for their hLDH5 inhibition activity. Enzymatic assays revealed that, among the ten selected compounds, two proved to efficiently inhibit enzyme activity with IC50 values in the micromolar range. These results demonstrate the validity of the methodologies we followed, encouraging the application of larger virtual screening studies and further refinements of the platform. Furthermore, the two active compounds herein described may be considered as interesting leads for the development of new and more efficient LDH inhibitors.
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. carlotta.granchi@farm.unipi.it.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Granchi
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. alice.capecchi@outlook.it.
authors.forename: Alice
authors.initials: A
authors.lastname: Capecchi
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Del Frate
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. adriano.martinelli@farm.unipi.it.
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. marco.macchia@farm.unipi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. filippo.minutolo@farm.unipi.it.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.affiliation: Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. tiziano.tuccinardi@farm.unipi.it.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000648:ultrastructure*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase
keywords: LDH inhibitors; docking; virtual screening