A Fragment-Based Approach to Identifying S-Adenosyl-l-methionine -Competitive Inhibitors of Catechol O-Methyl Transferase (COMT).

Abstract

Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson's disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.

Design of Potent and Druglike Nonphenolic Inhibitors for Catechol O-Methyltransferase Derived from a Fragment Screening Approach Targeting the S-Adenosyl-l-methionine Pocket

“…Following this screening/validation cascade we identified three pyrazole derivatives as fragment hits (Table ) with high ligand efficiencies (LE) . It is worth noting that we found similar starting points to the ones recently reported, in particular fragment 1 . This supports our findings, and it is not surprising since, unlike the high-throughput screening libraries, fragment libraries typically contain commercially available molecules selected with similar property criteria …”

“…20 It is worth noting that we found similar starting points to the ones recently reported, in particular fragment 1. 21 This supports our findings, and it is not surprising since, unlike the high-throughput screening libraries, fragment libraries typically contain commercially available molecules selected with similar property criteria. 14 In order to avoid interspecies differences in our hit to lead optimization process, we performed cocrystallization efforts with humanized rat COMT as this surrogate crystallizes better than human COMT and yields data relevant to human.…”

Inhibition of catechol-O-methyltransferase by natural pentacyclic triterpenes: structure–activity relationships and kinetic mechanism

“…Thus, the decrease of lipophilicity of ring A did not enhance COMT inhibition. In spite of minor difference in the ring E substitution position of C-29 and C-30 methyl groups, ursolic acid (7, IC 50 ¼ 15.13 ± 1.35 lM) displayed $3-fold lower inhibitory potency than oleanolic acid (1). Introducing hydroxyl into ring A of ursolic acid (7) can weaken COMT inhibition, as it did in the case of asiatic acid (8, IC 50 ¼ 43.11 ± 5.92 lM).…”

“…2.1.6) is a bisubstrate enzyme, that catalyses methyl transfer from S-adenosyl-L-methionine (SAM) to one of the hydroxyls of catecholamine neurotransmitters dopamine, epinephrine and norepinephrine, and catechol oestrogens, resulting in termination of their biological activity 1 , 2 . The catalytic site consisted of SAM and catechol binding pockets connected by a narrow channel through which methyl transfer occurs, where the SAM site proved to be deeply embedded 1 . COMT followed an ordered reaction mechanism where SAM bound first to the enzyme and the catechol substrate followed by release of the products in the reverse order 3 .…”

Síntese e exploração de múltiplos vetores sintéticos em fragmentos \"heteroaromáticos do futuro\"

“…A eficiência de ligação (LE = 1.36 × pIC50/átomos pesados) se refere a contribuição energética da interação de cada átomo pesado em uma determinada molécula com a macromolécula. 7 Ou seja, é um método capaz de solucionar algumas das dificuldades encontradas em processos de HTS, tais como, a presença de grupos funcionais desnecessários para a atividade, ou seja, grupos que não realizam contribuem para interação com a macromolécula, podendo então interferir negativamente com a energia de ligação, resultando em ambiguidade em resultados de atividade e dificultar o processo de otimização de estruturas hit para leads. Em outras palavras, além de "estruturas privilegiados", existem "estruturas desprivilegiados" que podem acessar áreas de espaço químico não exploradas e têm a vantagem adicional de evitar a sobreposição com a cobertura de patentes dos concorrentes?…”