Identification of Lactate Dehydrogenase 5 Inhibitors using Pharmacophore- Driven Consensus Docking

Title:Identification of Lactate Dehydrogenase 5 Inhibitors using Pharmacophore- Driven Consensus Docking

Volume: 14 Issue: 2

Author(s): Giulio Poli*, Andrea Scarpino, Mohamed Aissaoui, Carlotta Granchi, Filippo Minutolo, Adriano Martinelli and Tiziano Tuccinardi

Affiliation:

• Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100, Siena,Italy

Keywords: LDH inhibitors, virtual screening, docking, molecular dynamic simulations, pharmacophore modeling, hit identification.

Abstract: Background: Human lactate dehydrogenase 5 (hLDH5) represents a promising anticancer target, particularly for the treatment of hypoxic tumors, where it is often hyperexpressed. In fact, by catalyzing the reduction of pyruvate to lactate, hLDH5 allows the survival of tumor cells under hypoxic conditions by means of glycolysis. Despite the efforts dedicated to the identification and development of hLDH5 inhibitors, only few compounds showing promising activity in cancer cell lines have been reported.

Objective: In the present study, we developed a virtual screening (VS) protocol aimed at identifying new small molecule inhibitors of hLDH5.

Method: The VS strategy consisted in a pharmacophore-driven consensus docking (CD) approach, combining a structure-based pharmacophore screening and CD protocol employing three different docking methods.

Results: The VS protocol was applied to filter the Enamine commercial database and allowed the selection of three candidate ligands to be subjected to hLDH5 inhibition assays. One of the selected compounds showed a promising activity, compared to its low molecular weight, with an IC50 of 180.7 ± 16.5 µM.

Conclusion: We identified a new small-molecule inhibitor of hLDH5 that can be considered as a new lead for the development of potent hLDH5 inhibitors. Moreover, these results demonstrate the reliability of the VS protocol developed.

Cite this article as:

Poli Giulio*, Scarpino Andrea, Aissaoui Mohamed, Granchi Carlotta, Minutolo Filippo, Martinelli Adriano and Tuccinardi Tiziano, Identification of Lactate Dehydrogenase 5 Inhibitors using Pharmacophore- Driven Consensus Docking, Current Bioactive Compounds 2018; 14 (2) . https://dx.doi.org/10.2174/1573407213666170208102317