Abstract
Dopa decarboxylase (DDC), a pyridoxal 5′-phosphate (PLP) enzyme responsible for the biosynthesis of dopamine and serotonin, is involved in Parkinson's disease (PD). PD is a neurodegenerative disease mainly due to a progressive loss of dopamine-producing cells in the midbrain. Co-administration of L-Dopa with peripheral DDC inhibitors (carbidopa or benserazide) is the most effective symptomatic treatment for PD. Although carbidopa and trihydroxybenzylhydrazine (the in vivo hydrolysis product of benserazide) are both powerful irreversible DDC inhibitors, they are not selective because they irreversibly bind to free PLP and PLP-enzymes, thus inducing diverse side effects. Therefore, the main goals of this study were (a) to use virtual screening to identify potential human DDC inhibitors and (b) to evaluate the reliability of our virtual-screening (VS) protocol by experimentally testing the “in vitro” activity of selected molecules. Starting from the crystal structure of the DDC-carbidopa complex, a new VS protocol, integrating pharmacophore searches and molecular docking, was developed. Analysis of 15 selected compounds, obtained by filtering the public ZINC database, yielded two molecules that bind to the active site of human DDC and behave as competitive inhibitors with Ki values ≥10 µM. By performing in silico similarity search on the latter compounds followed by a substructure search using the core of the most active compound we identified several competitive inhibitors of human DDC with Ki values in the low micromolar range, unable to bind free PLP, and predicted to not cross the blood-brain barrier. The most potent inhibitor with a Ki value of 500 nM represents a new lead compound, targeting human DDC, that may be the basis for lead optimization in the development of new DDC inhibitors. To our knowledge, a similar approach has not been reported yet in the field of DDC inhibitors discovery.
Highlights
Parkinson’s disease (PD) is the most extensively studied pathology within a group of syndromes called ‘‘motor system disorders’’, whose etiology can be traced back to the loss of dopaminergic neurons of the substantia nigra in the midbrain [1]
On the basis of assays performed on a pig kidney extract [20], they were clustered in inactive (31 compounds causing a loss of Dopa decarboxylase (DDC) activity,10% at 2.2 mM concentration), poorly active (33 compounds causing a loss of DDC activity $10% at 2.2 mM concentration), moderately active (29 compounds causing a loss of DDC activity $10% at a concentration in the range 220– 440 mM), and highly active (9 compounds causing a loss of DDC activity $10% at a concentration,110 mM)
Aromatic hydrazine derivatives are used in combination with L-Dopa to treat the symptoms of PD or Parkinson-like symptoms
Summary
Parkinson’s disease (PD) is the most extensively studied pathology within a group of syndromes called ‘‘motor system disorders’’, whose etiology can be traced back to the loss of dopaminergic neurons of the substantia nigra in the midbrain [1]. As the symptoms become more severe, patients progressively encounter difficulties in walking, talking, or even completing the simplest tasks; usually, this condition interferes strongly with most daily activities. At present there is no cure for PD, but a variety of palliatives reducing the severity of disease symptoms exists [2]. In order to replenish dopamine levels at the central nervous system (CNS), LDopa is usually administered. The latter is converted to dopamine by Dopa decarboxylase (DDC, E.C. 4.1.1.28), a pyridoxal-59phosphate (PLP)-dependent enzyme, which is abundant in the CNS and in the kidney [3]. The crystal structures of DDC, both ligand-free and in complex with the antiParkinson drug carbidopa, have been solved [13]
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