Binding of phosphinate and phosphonate inhibitors to aspartic proteases: a first-principles study.
Phosphinate and phosphonate derivatives are potent inhibitors of aspartic proteases (APs). The affinity for the enzyme might be caused by the presence of low barrier hydrogen bonds between the ligand and the catalytic Asp dyad in the cleavage site. We have used density functional theory calculations along with hybrid quantum mechanics/molecular mechanics Car-Parrinello molecular dynamics simulations to investigate the hydrogen-bonding pattern at the binding site of the complexes of human immunodeficiency virus type-1 AP and the eukaryotic endothiapepsin and penicillopepsin. Our calculations are in fair agreement with the NMR data available for endothiapepsin (Coates et al. J. Mol. Biol. 2002, 318, 1405-1415) and show that the most stable active site configuration is the diprotonated, negatively charged form. In the viral complex both protons are located at the catalytic Asp dyad, while in the eukaryotic complexes the proton shared by the closest oxygen atoms is located at the phosphinic/phosphonic group.
International School for Advanced Studies and INFM-Democritos Modeling Center for Research in Atomistic Simulation, via Beirut 2-4 34014 Trieste, Italy.
Pietro
P
Vidossich
Paolo
P
Carloni
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology; D010721:Phosphinic Acids / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D063065:Organophosphonates; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases