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 a,b-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.

Grazioso, G., Legnani, L., Toma, L., Ettari, R., Micale, N., De Micheli, C. (2012). Mechanism of falcipain-2 inhibition by a,b-unsaturated benzo[1,4]diazepin-2-one methyl ester. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 26(9), 1035-1043 [10.1007/s10822-012-9596-4].

Mechanism of falcipain-2 inhibition by a,b-unsaturated benzo[1,4]diazepin-2-one methyl ester

LEGNANI, LAURA;
2012

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 a,b-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.
Articolo in rivista - Articolo scientifico
Falcipain-2 inhibitors; Mechanistic study; Michael reaction; ONIOM calculations;
English
1035
1043
9
Grazioso, G., Legnani, L., Toma, L., Ettari, R., Micale, N., De Micheli, C. (2012). Mechanism of falcipain-2 inhibition by a,b-unsaturated benzo[1,4]diazepin-2-one methyl ester. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 26(9), 1035-1043 [10.1007/s10822-012-9596-4].
Grazioso, G; Legnani, L; Toma, L; Ettari, R; Micale, N; De Micheli, C
File in questo prodotto:
File Dimensione Formato  
repr155.pdf

Solo gestori archivio

Dimensione 509.95 kB
Formato Adobe PDF
509.95 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/352007
Citazioni
  • Scopus 28
  • ???jsp.display-item.citation.isi??? 26
Social impact