title: Mechanism of falcipain-2 inhibition by α,β-unsaturated benzo[1,4]diazepin-2-one methyl ester.
abstract: Falcipain-2 (FP-2) is a papain-family cysteine protease of Plasmodium falciparum whose primary function is to degrade the host red cell hemoglobin, within the food vacuole, in order to provide free amino acids for parasite protein synthesis. Additionally it promotes host cell rupture by cleaving the skeletal proteins of the erythrocyte membrane. Therefore, the inhibition of FP-2 represents a promising target in the search of novel anti-malarial drugs. A potent FP-2 inhibitor, characterized by the presence in its structure of the 1,4-benzodiazepine scaffold and an α,β-unsaturated methyl ester moiety capable to react with the Cys42 thiol group located in the active site of FP-2, has been recently reported in literature. In order to study in depth the inhibition mechanism triggered by this interesting compound, we carried out, through ONIOM hybrid calculations, a computational investigation of the processes occurring when the inhibitor targets the enzyme and eventually leads to an irreversible covalent Michael adduct. Each step of the reaction mechanism has been accurately characterized and a detailed description of each possible intermediate and transition state along the pathway has been reported.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy. giovanni.grazioso@unimi.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grazioso
authors.forename: Laura
authors.initials: L
authors.lastname: Legnani
authors.forename: Lucio
authors.initials: L
authors.lastname: Toma
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.forename: Nicola
authors.initials: N
authors.lastname: Micale
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000201:enzymology
chemical_list: D000962:Antimalarials; D001570:Benzodiazepinones; D015853:Cysteine Proteinase Inhibitors; D004952:Esters; D003546:Cysteine Endopeptidases; C416224:falcipain 2