title: Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders.
abstract: Catechol-O-methyltransferase (COMT) is of great importance in pharmacology because it catalyzes the metabolism (methylation) of endogenous and xenobiotic catechols. Moreover, inhibition of COMT is the drug target in the management of central nervous system (CNS) disorders such as Parkinson's disease due to its role in regulation of the dopamine level in the brain. The X-ray crystal structures for COMT have been available since 1994. The active sites for cofactor and substrate/inhibitor binding are well resolved to an atomic level, providing valuable insights into the catalytic mechanisms as well as the role of magnesium ions in catalysis. Determination of how the substrates/inhibitors bind to the protein leads to a structure-based approach that has resulted in potent and selective inhibitors. This review focuses on the design of two types of inhibitors (nitrocatechol-type and bisubstrate inhibitors) for COMT using the protein structures.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Ma
authors.forename: Hongming
authors.initials: H
authors.lastname: Liu
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D002394:Catechol O-Methyltransferase / Q000737:chemistry / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D002490:Central Nervous System / Q000187:drug effects* / Q000201:enzymology; D002491:Central Nervous System Agents / Q000737:chemistry / Q000494:pharmacology*; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D002491:Central Nervous System Agents; D004791:Enzyme Inhibitors; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase
keywords: COMT; catechol-O-methyltransferase; crystal structure; drug discovery; drug metabolism