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Expanding the chemical space of human serine racemase inhibitors.

Abstract：

:Serine racemase, the enzyme responsible for d-serine synthesis in the central nervous system, has been identified as a potential therapeutic target to treat N-methyl-d-aspartate receptors-related pathologies. The search for specific inhibitors of the enzyme has revealed that serine racemase is a difficult target, with the best inhibitor currently identified, 2,2-dichloromalonate, showing a Ki of 19 μM. In order to expand the chemical space of hit compounds, we have performed an in silico structure-based screening campaign on a filtered ZINC library applying the FLAP software. The identified hits were docked with GOLD and re-scored with HINT, and the most promising molecules experimentally evaluated on recombinant human serine racemase. Two inhibitors, with chemical structures totally unrelated to inhibitors described so far showed Ki values of about 1.5 mM.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Dellafiora L,Marchetti M,Spyrakis F,Orlandi V,Campanini B,Cruciani G,Cozzini P,Mozzarelli A

doi

10.1016/j.bmcl.2015.07.081

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

4297-303

issue

19

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)00785-4

journal_volume

25

pub_type

杂志文章

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