HIV-l protease

The HIV-l protease is a remarkable viral imitation of mammalian aspartic proteases It is a dimer of identical subunits that mimics the two-lobed monomeric structure of pepsin and other aspartic proteases. The HIV-l protease subunits are 99-residue polypeptides that are homologous with the individual domains of the monomeric proteases. Structures determined by X-ray diffraction studies reveal that the active site of HIV-l protease is formed at the interface of the homodimer and consists of two aspartate residues, designated Asp and Asp one contributed by each subunit (Figure 16.29). In the homodimer, the active site is covered by two identical flaps, one from each subunit, in contrast to the monomeric aspartic proteases, which possess only a single active-site flap. 

A class of HIV-l protease inhibitors extensively examined in our department are the cyclic sulfamides [73,74]. These compounds are related to our linear 1,2-dihydroxyethylene inhibitors described above in that they are also derived from L-mannitol and employ a 1,2-dihydroxyethylene transition-state isostere. These cyclic inhibitors are comprised of seven-membered rings where the sulfonyl oxygens are designed to displace a structural water in the enzyme when the inhibitors bind to the active site [73]. The synthesis of the... 

Isoquercitrin (= Quercetin 3-O-glucosidc) Widespread Gossypium herbaceum (Malvaceae), Morns alba (Moraceae) HIV-l protease (< 108 pM) [42]... 

The humanized mouse model is used for safety assessment of drugs that affect lipid profiles as a side effect (and thereby possibly influence the risk of atherosclerosis and, subsequently, myocardial infarction). A typical example is the disturbed lipid profile and increased risk of myocardial infarction experienced by AIDS patients following the long-term use of HIV-l-protease inhibitors [16,17]. 

Markowitz M, Conant M, Hurley A, Schluger R, Duran M, Peterkin J, Chapman S, Patick A, Hendricks A, Yuen GJ, Hoskins W, Clendeninn N, Ho DD. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-l protease, to treat HIV infection. J Infect Dis 1998 177(6) 1533-40. 

Figure IS. (a) Stereoview of the contour at —5 kcal/mol for the GRID calculation using a water probe (cyan) and the HIV-1 protease crystal structure [72]. Inhibitor 29 (yellow, first binding mode), an inserted water molecule (red), and Asp29 (magenta) are shown, (b) Stereoview of the contour at —5 kcal/mol for the GRID calculation using a water probe (cyan) and the HIV-l protease crystal structure [72]. Inhibitor 29 (yellow, second binding mode), an inserted water molecule (red), and Gly48 (magenta) are shown.

Caruifolin A (germacranolide sesquiterpene) Artemisia caruifolia (Asteraceae) HIV-l protease (< 50% inhibition at 376 pM) [51]... 

Epipomolie acid (triterpene) Geum japonica (Rosaceae) HIV-l protease (42 % inhibition at 38 pM) [49, 55]... 

Wallqvist, A., Jernigan, R. L. Covell, D. G. (1995). A preference-based free-energy parameterization of enzyme-inhibitor binding. Applications to HIV-l-protease inhibitor design. Protein Science 4, 1881-1903. 

Figure 4.8. Hydrogen bonds between a prototypical aspartic protease inhibitor (acetylpepstatin) and HIV-l protease. The residues are labeled at the C-p position (C-a for glycine). The residues labeled 25-50 are from monomer A, those labeled 225-250 are from monomer B, and those labeled...

Determine the optimal time step for the MD simulations (see above section on Computer Model Validation re HIV-l protease). 

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