New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C⁸ Substitution in Structural Analogues of S-Adenosylmethionine

Abstract

S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C8-substituted adenine analogues bound in the active site.

Novel S-adenosyl-L-methionine decarboxylase inhibitors as potent antiproliferative agents against intraerythrocytic Plasmodium falciparum parasites

“…3A) shows similar interactions to other AdoMetDC substrate analogues (Fig. 3B) (McCloskey et al, 2009). Moreover, conformational search analysis of the N -(Z)-4-aminobutenyl- N -methyl tail of Genz-644131 showed that the lowest absolute energy of the Genz-644131 syn conformation is reached when the tail assumes the predicted binding conformation (-126.9 kcal/mol) (Fig.…”

Epigenetics in autoimmune disorders: Highlights of the 10th Sjögren's Syndrome Symposium

“…Finally, Wesley Brooks (Drug Discovery, Tampa, USA) reported that blocking the human S-Adenosylmethionine (SAM) Decarboxylase with a specific inhibitor prevents the SAM's degradation [28]. As a consequence this new drug should reduce the DNA methylation observed in autoimmune diseases by providing more SAM to the cell.…”

Discovery of novel inhibitors of human S-adenosylmethionine decarboxylase based on in silico high-throughput screening and a non-radioactive enzymatic assay

“…The docked model showed that AO-476/43250076 binds the enzyme with interactions similar to known inhibitors15. The scaffold of this compound is quite different from previously known AdoMetDC inhibitors131554, and therefore could represent a novel class of AdoMetDC inhibitors. The relatively low potency of this compound indicates that further optimization is necessary, and enlightened by the docking analysis of the known inhibitor in this study, a reasonable way is to add a functional group that could form a Schiff base to the active site pyruvoyl group.…”

“…S5) to confirm that the compound is indeed effective and the PEPC-MDH system is not inhibited by chance. Therefore, we feel that this assay would accelerate the discovery of novel AdoMetDC inhibitors, considering most known AdoMetDC inhibitors are based on the deoxyadenosine group1554.…”