Human dihydroorotate dehydrogenase (hDHODH) is an enzyme belonging to a flavin mononucleotide (FMN)-dependent family involved in de novo pyrimidine biosynthesis, a key biological pathway for highly proliferating cancer cells and pathogens. In fact, hDHODH proved to be a promising therapeutic target for the treatment of acute myelogenous leukemia, multiple myeloma, and viral and bacterial infections; therefore, the identification of novel hDHODH ligands represents a hot topic in medicinal chemistry. In this work, we reported a virtual screening study for the identification of new promising hDHODH inhibitors. A pharmacophore-based approach combined with a consensus docking analysis and molecular dynamics simulations was applied to screen a large database of commercial compounds. The whole virtual screening protocol allowed for the identification of a novel compound that is endowed with promising inhibitory activity against hDHODH and is structurally different from known ligands. These results validated the reliability of the in silico workflow and provided a valuable starting point for hit-to-lead and future lead optimization studies aimed at the development of new potent hDHODH inhibitors.

Identification of Human Dihydroorotate Dehydrogenase Inhibitor by a Pharmacophore-Based Virtual Screening Study

Galati, Salvatore
First
;
Sainas, Stefano;Giorgis, Marta;Boschi, Donatella;Lolli, Marco L;
2022-01-01

Abstract

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme belonging to a flavin mononucleotide (FMN)-dependent family involved in de novo pyrimidine biosynthesis, a key biological pathway for highly proliferating cancer cells and pathogens. In fact, hDHODH proved to be a promising therapeutic target for the treatment of acute myelogenous leukemia, multiple myeloma, and viral and bacterial infections; therefore, the identification of novel hDHODH ligands represents a hot topic in medicinal chemistry. In this work, we reported a virtual screening study for the identification of new promising hDHODH inhibitors. A pharmacophore-based approach combined with a consensus docking analysis and molecular dynamics simulations was applied to screen a large database of commercial compounds. The whole virtual screening protocol allowed for the identification of a novel compound that is endowed with promising inhibitory activity against hDHODH and is structurally different from known ligands. These results validated the reliability of the in silico workflow and provided a valuable starting point for hit-to-lead and future lead optimization studies aimed at the development of new potent hDHODH inhibitors.
2022
27
12
3660
3670
https://www.mdpi.com/1420-3049/27/12/3660
human dihydroorotate dehydrogenase; pharmacophore model; virtual screening; Dihydroorotate Dehydrogenase; Drug Evaluation, Preclinical; Enzyme Inhibitors; Humans; Ligands; Molecular Docking Simulation; Receptors, Drug; Reproducibility of Results; Oxidoreductases Acting on CH-CH Group Donors
Galati, Salvatore; Sainas, Stefano; Giorgis, Marta; Boschi, Donatella; Lolli, Marco L; Ortore, Gabriella; Poli, Giulio; Tuccinardi, Tiziano
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1879146
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