Identification by Virtual Screening and In Vitro Testing of Human DOPA Decarboxylase Inhibitors

被引:56
作者
Daidone, Frederick [1 ]
Montioli, Riccardo [2 ]
Paiardini, Alessandro [1 ]
Cellini, Barbara [2 ]
Macchiarulo, Antonio [3 ]
Giardina, Giorgio [1 ]
Bossa, Francesco [1 ]
Voltattorni, Carla Borri [2 ]
机构
[1] Univ Roma La Sapienza, Dept Biochem Sci A Rossi Fanelli, Rome, Italy
[2] Univ Verona, Dept Life Sci & Reprod, I-37100 Verona, Italy
[3] Univ Perugia, Dept Chem & Drug Technol, I-06100 Perugia, Italy
关键词
3,4-DIHYDROXYPHENYLALANINE DECARBOXYLASE; BENSERAZIDE; MUTATION; PLASMA; HOMOCYSTEINE; METABOLISM; CARBIDOPA; EFFICIENT; DOCKING; LEADS;
D O I
10.1371/journal.pone.0031610
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 K-i values >= 10 mu M. 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 K-i 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 K-i 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.
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页数:15
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