Interactions of the dimeric triad of HIV-1 aspartyl protease with inhibitors.
Strong hydrogen-bonding forces between the Thr26 and Thr26' of the protease stabilize the internal cage of the dimeric triad of the aspartyl HIV-1 protease (Asp25Thr26Gly27 and Asp25' Thr26'Gly27', respectively). The interaction of reversible inhibitors of HIV-1 protease is based on (i) strong hydrogen-bonding forces between the main chain (--CONH--) oxygen atoms of Gly27 and/or Gly27' and hydrogen-bond donating moieties of a drug, and (ii) hydrogen bonds between the oxygen of the catalytic Asp25 and/or Asp25' carboxylates and aliphatic hydroxyl groups of a drug. The free entry of natural substrates into the active-site cavity is sterically hindered by inhibitors, so that the catalytic Asp carboxylates cannot interact with natural substrates. Irreversible inhibitors interact with the nucleophilic carboxylate moiety of Asp25 of HIV-1 protease by covalent bonding.
Mager
Peter P
PP
Research Group of Pharmacochemistry, Institute of Pharmacology and Toxicology of the University, Saxony, Germany.
De Clercq
Erik
E
Froeyen
Matheus
M
Reinhardt
Robert
R
D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure
D004791:Enzyme Inhibitors; D016282:Aspartic Acid Endopeptidases