title: Theoretical study on the mechanism of a ring-opening reaction of oxirane by the active-site aspartic dyad of HIV-1 protease.
abstract: Two possible mechanisms of the irreversible inhibition of HIV-1 protease by epoxide inhibitors are investigated on an enzymatic model using ab initio (MP2) and density functional theory (DFT) methods (B3LYP, MPW1K and M05-2X). The calculations predict the inhibition as a general acid-catalyzed nucleophilic substitution reaction proceeding by a concerted SN2 mechanism with a reaction barrier of ca. 15-21 kcal mol(-1). The irreversible nature of the inhibition is characterized by a large negative reaction energy of ca. -17-(-24) kcal mol(-1). A mechanism with a direct proton transfer from an aspartic acid residue of the active site onto the epoxide ring has been shown to be preferred compared to one with the proton transfer from the acid catalyst facilitated by a bridging catalytic water molecule. Based on the geometry of the transition state, structural data important for the design of irreversible epoxide inhibitors of HIV-1 protease were defined. Here we also briefly discuss differences between the epoxide ring-opening reaction in HIV-1 protease and epoxide hydrolase, and the accuracy of the DFT method used.
authors.affiliation: International School for Advanced Studies (SISSA) and Democritos Modeling Center for Research in Atomistic Simulation (INFM), via Beirut 2-4, 34014 Trieste, Italy. chemkona@savba.sk
authors.forename: Juraj
authors.initials: J
authors.lastname: Kóna
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D001665:Binding Sites; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry* / Q000494:pharmacology; D005027:Ethylene Oxide / Q000737:chemistry* / Q000494:pharmacology; D016333:HIV Protease / Q000737:chemistry* / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011789:Quantum Theory; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004852:Epoxy Compounds; D017320:HIV Protease Inhibitors; D001224:Aspartic Acid; D004851:Epoxide Hydrolases; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D005027:Ethylene Oxide