Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT)

Harrison, Scott T.; Poslusney, Michael S.; Mulhearn, James; Zhao, Zhijian; Kett, Nathan R.; Schubert, Jeffrey W.; Melamed, Jeffrey Y.; Allison, Timothy J.; Patel, Sangita; Sanders, John M.; Sharma, Sujata; Smith, Robert F.; Hall, Dawn L.; Robinson, R.; Sachs, Nancy A.; Hutson, Pete H.; Wolkenberg, S. E.; Barrow, James C.

doi:10.1021/ml500502d

Cited by 33 publications

(40 citation statements)

References 36 publications

(61 reference statements)

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“…Given its role in catechol catabolism, COMT represents an important drug target for treating neurological disorders such as Parkinson’s Disease and schizophrenia [ 45 , 49 ]. The COMT inhibitors identified in the survey represent catechol or catechol-like substrate analogs that mimic the binding of the substrate in the active site [ 46 , 50 , 51 , 52 ], as illustrated by the ternary complex of the enzyme bound to AdoMet and 3,5-dinitrocatechol (DNC) ( Figure 1 a). The interaction distances between the AdoMet methyl group and the oxygen atoms in the catechol analog inhibitors (R(C∙∙∙O) = 2.5–2.8 Å) are considerably shorter than the sum of the carbon and oxygen van der Waals radii (3.25 Å), indicative of strong tetrel bonding.…”

Section: Resultsmentioning

confidence: 99%

Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases

Trievel

Scheiner

2018

Molecules

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Tetrel bonds represent a category of non-bonding interaction wherein an electronegative atom donates a lone pair of electrons into the sigma antibonding orbital of an atom in the carbon group of the periodic table. Prior computational studies have implicated tetrel bonding in the stabilization of a preliminary state that precedes the transition state in SN2 reactions, including methyl transfer. Notably, the angles between the tetrel bond donor and acceptor atoms coincide with the prerequisite geometry for the SN2 reaction. Prompted by these findings, we surveyed crystal structures of methyltransferases in the Protein Data Bank and discovered multiple instances of carbon tetrel bonding between the methyl group of the substrate S-adenosylmethionine (AdoMet) and electronegative atoms of small molecule inhibitors, ions, and solvent molecules. The majority of these interactions involve oxygen atoms as the Lewis base, with the exception of one structure in which a chlorine atom of an inhibitor functions as the electron donor. Quantum mechanical analyses of a representative subset of the methyltransferase structures from the survey revealed that the calculated interaction energies and spectral properties are consistent with the values for bona fide carbon tetrel bonds. The discovery of methyl tetrel bonding offers new insights into the mechanism underlying the SN2 reaction catalyzed by AdoMet-dependent methyltransferases. These findings highlight the potential of exploiting these interactions in developing new methyltransferase inhibitors.

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Section: Resultsmentioning

confidence: 99%

Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases

Trievel

Scheiner

2018

Molecules

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“…At least ten experimental crystal structures[ 15 , 43 , 75 – 79 ] of COMT have been solved with bound inhibitors ranging from dinitro to coumarine in nature along with SAM and Mg 2+ in the active site at resolutions ranging from 1.3 to 2.4 Å. On average, the bidentate substrate analogue in these structures has two Mg 2+ -O bond distances averaging around 2.16 Å that are comparable to the 2.12 Å average distance for the remaining species in the active site (Asp141, Asp169, Asn170, and H 2 O) that coordinate Mg 2+ .…”

Section: Resultsmentioning

confidence: 99%

Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase

2016

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Catechol O-methyltransferase (COMT) is a SAM- and Mg2+-dependent methyltransferase that regulates neurotransmitters through methylation. Simulations and experiments have identified divergent catecholamine substrate orientations in the COMT active site: molecular dynamics simulations have favored a monodentate coordination of catecholate substrates to the active site Mg2+, and crystal structures instead preserve bidentate coordination along with short (2.65 Å) methyl donor-acceptor distances. We carry out longer dynamics (up to 350 ns) to quantify interconversion between bidentate and monodentate binding poses. We provide a systematic determination of the relative free energy of the monodentate and bidentate structures in order to identify whether structural differences alter the nature of the methyl transfer mechanism and source of enzymatic rate enhancement. We demonstrate that the bidentate and monodentate binding modes are close in energy but separated by a 7 kcal/mol free energy barrier. Analysis of interactions in the two binding modes reveals that the driving force for monodentate catecholate orientations in classical molecular dynamics simulations is derived from stronger electrostatic stabilization afforded by alternate Mg2+ coordination with strongly charged active site carboxylates. Mixed semi-empirical-classical (SQM/MM) substrate C-O distances (2.7 Å) for the bidentate case are in excellent agreement with COMT X-ray crystal structures, as long as charge transfer between the substrates, Mg2+, and surrounding ligands is permitted. SQM/MM free energy barriers for methyl transfer from bidentate and monodentate catecholate configurations are comparable at around 21–22 kcal/mol, in good agreement with experiment (18–19 kcal/mol). Overall, the work suggests that both binding poses are viable for methyl transfer, and accurate descriptions of charge transfer and electrostatics are needed to provide balanced relative barriers when multiple binding poses are accessible, for example in other transferases.

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“…Besides nitrocatechols, other scaffolds that have given rise to COMT inhibitors are generically shown in Figure 2 including 8-hydroxyquinazolinones 4, 14 8-hydroxyquinolines 5, 15 and 3-hydroxy-4-pyrimidinones 6. 16 As reported by Harrison et. al, 16 a particular series of N-aryl 4-pyridones arose from a formal removal of the thiomorpholine ring from the initial screening hit 7.…”

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confidence: 72%

Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase

Ernst

Akuma

et al. 2019

ACS Med. Chem. Lett.

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A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC 50 s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.

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Synthesis and Evaluation of Heterocyclic Catechol Mimics as Inhibitors of Catechol-O-methyltransferase (COMT)

Cited by 33 publications

References 36 publications

Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases

Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S-Adenosylmethionine-Dependent Methyltransferases

Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase

Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase

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