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

Abstract

A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported. These compounds represent a novel series of potent COMT inhibitors that might be further optimized to new drugs useful for the treatment of Parkinson's disease, as adjuncts in levodopa based therapy, or for the treatment of schizophrenia.

Coupling S-adenosylmethionine–dependent methylation to growth: Design and uses

“…SAM-dependent Mtases participate in many important cellular functions and are targeted by a number of drug development programs (such as DNA or histone Mtase inhibitors) [6]. We applied our selection system on catechol O-methyltransferase (Comt), a known drug target for treating Parkinson's disease [5]. Cells bearing human Comt were evolved to grow at high rates using ALE (Fig 2E).…”

“…In fact, SAM is one of the most commonly used cofactors in cellular metabolism, second only to ATP [3]. SAM-dependent Mtases have become an important enzyme category, used either as biocatalysts, as part of fermentative production pathways in biotechnical and chemical industries [2–4], or as drug targets in the pharmaceutical industry [5,6].…”

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

“…Of these, the compounds ZINC63625100_413, ZINC39411941_412, ZINC63234426_254, ZINC63637968_451, and ZINC64019452_303, displayed in Figure 24, have the highest score and can form important interactions with the active site, being considered potential COMT inhibitors [149]. Lerner et al applied a fragment screening in silico approach to identify novel compounds that specifically targeted the SAM binding site of the COMT catalytic site (PDB#5K05) [150]. From an initial set of 6000 compounds, the structures that violated the Lipinski's rules were filtered, 600 fragments were selected based on the affinity towards the target and submitted to further molecular docking studies [150].…”

“…Lerner et al applied a fragment screening in silico approach to identify novel compounds that specifically targeted the SAM binding site of the COMT catalytic site (PDB#5K05) [150]. From an initial set of 6000 compounds, the structures that violated the Lipinski's rules were filtered, 600 fragments were selected based on the affinity towards the target and submitted to further molecular docking studies [150]. This novel approach identified several moieties that were further studied in vitro and displayed high COMT inhibitory activity, which can be even further enhanced through structural optimization [150].…”

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

“…The indirect dopamine agonist amphetamine impaired recognition memory in controls but ameliorated recognition memory in COMT‐Val transgenics, supporting the hypothesized inverted U relationship between extent of PFC‐mediated dopaminergic transmission and cognitive function (Tunbridge et al, ; Papaleo et al, ; Harrison, ). The clinical utility of existing COMT inhibitors for treating cognitive deficits of schizophrenia is restricted due to limited brain penetration and/or are characterized by acidity and polarity profiles that challenge their CNS drug development potential (Lerner et al, ). Partial deletion of PRODH in mice is associated with deficits in prepulse inhibition and cued/contextual learning, as well as increased sensitivity to the disruptive effects of the COMT inhibitor tolcapone on working memory in mice (Gogos et al, ; Paterlini et al, ).…”