A symmetric inhibitor binds HIV-1 protease asymmetrically.
Potential advantages of C2-symmetric inhibitors designed for the symmetric HIV-1 protease include high selectivity, potency, stability, and bioavailability. Pseudo-C2-symmetric monools and C2-symmetric diols, containing central hydroxymethylene and (R,R)-dihydroxyethylene moieties flanked by a variety of hydrophobic P1/P1' side chains, were studied as HIV-1 protease inhibitors. The monools and diols were synthesized in 8-10 steps from D-(+)-arabitol and D-(+)-mannitol, respectively. Monools with ethyl or isobutyl P1/P1' side chains were weak inhibitors of recombinant HIV-1 protease (Ki > 10 microM), while benzyl P1/P1' side chains afforded a moderately potent inhibitor (apparent Ki = 230 nM). Diols were 100-10,000x more potent than analogous monools, and a wider range of P1/P1' side chains led to potent inhibition. Both classes of compounds exhibited lower apparent Ki values under high-salt conditions. Surprisingly, monool and diol HIV-1 protease inhibitors were potent inhibitors of porcine pepsin, a prototypical asymmetric monomeric aspartic protease. These results were evaluated in the context of the pseudosymmetric structure of monomeric aspartic proteases and their evolutionary kinship with the retroviral proteases. The X-ray crystal structure of HIV-1 protease complexed with a symmetric diol was determined at 2.6 A. Contrary to expectations, the diol binds the protease asymmetrically and exhibits 2-fold disorder in the electron density map. Molecular dynamics simulations were conducted beginning with asymmetric and symmetric HIV-1 protease/inhibitor model complexes. A more stable trajectory resulted from the asymmetric complex, in agreement with the observed asymmetric binding mode. A simple four-point model was used to argue more generally that van der Waals and electrostatic force fields can commonly lead to an asymmetric association between symmetric molecules.
Dreyer
G B
GB
Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Boehm
J C
JC
Chenera
B
B
DesJarlais
R L
RL
Hassell
A M
AM
Meek
T D
TD
Tomaszek
T A
TA
Lewis
M
M
D000438:Alcohols / Q000737:chemistry / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006018:Glycols / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D016333:HIV Protease / Q000187:drug effects* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010434:Pepsin A / Q000037:antagonists & inhibitors; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D000438:Alcohols; D004151:Dipeptides; D006018:Glycols; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; C079395:SK&F 108361; C026650:phenylalanylphenylalanine; D016333:HIV Protease; D010434:Pepsin A