title: Computational study on the inhibition mechanism of cruzain by nitrile-containing molecules.
abstract: Cysteine proteases from parasites as well as from mammals are promising drug targets for parasitic infections and systemic human diseases, respectively. Many reversible and irreversible inhibitors of this very large class of proteins have been designed. Among others, molecules with a nitrile moiety, which is a group that is susceptible to a nucleophilic attack by the enzyme, have been identified as good inhibitors. Although it is known that the nitrile group binds covalently to Cys25, there are no reports about the energetics involved in the mechanism of this process. Herein, density functional theory and quantum semi-empirical calculations were conducted in order to study the molecular recognition of cysteine proteases by nitrile-containing molecules. Results reported in this paper suggest an interaction that starts with a nucleophilic attack from the Cys25 to the inhibitor followed by a proton transfer from His162. Only one transition state was detected; however, we found the existence of an energy plateau in the potential energy surface. Based on the proposed mechanism, some structural features that could improve the biological activity of nitrile-containing molecules toward cysteine proteases are discussed.
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México 04510, DF, Mexico.
authors.forename: Oscar
authors.initials: O
authors.lastname: Méndez-Lucio
authors.forename: Antonio
authors.initials: A
authors.lastname: Romo-Mancillas
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo
mesh_terms: D000465:Algorithms; D000981:Antiprotozoal Agents / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011687:Purines / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D015800:Protozoan Proteins; D011687:Purines; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi