Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus 1 (HIV-1) protease is a prime target in the search for drugs to combat the AIDS virus. The enzyme functions as a C2-symmetric dimer, cleaving the gag and gag-pol viral polyproteins at distinct sites. The possession of a twofold axis passing through the active site, has led to the design of C2-symmetrical inhibitors in the form of substrate-based transition-state analogs. One of the most active compounds of this class of inhibitors is HOE/BAY 793, which contains a vicinal diol central unit [Budt, K.-H., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D. & Stowasser, B. & Winkler, I. (1990) European Patent application EP0428,849; Budt, K.-H., Hansen, J., Knolle, J., Meichsner, C., Ruppert, D., Paessens, A. & Stowasser B. (1993) IXth International Conference on AIDS; Budt, K.-H., Peyman, A., Hansen, J., Knolle, J., Meichsner, C., Paessens, A., Ruppert, D. & Stowasser, B. (1995) Bioorg. Med. Chem. 3, 559-571.] The structure of this inhibitor bound to HIV-1 protease, in two different crystal forms, has been solved at 0.24-nm resolution using X-ray crystallography. In both forms, the details of the inhibitor-protease interactions revealed an overall asymmetric binding mode, especially between the central diol unit and the active-site aspartates. The main binding interactions comprise several specific H-bonds and hydrophobic contacts, which rationalize many of the characteristics of the structure/activity relationship in the class of vicinal diol inhibitors. In a general analysis of the mobility of the flap regions, which cover the active site and participate directly in binding, using our structures and the HIV protease models present in the Brookhaven databank, we found that in most structures the flexibility of the flaps is limited by local crystal contacts. However, in one of the structures presented here, no significant crystal contacts to the flap regions were present, and as a result the flexibility of the inhibitor bound flaps increased significantly. This suggests that the mobility and conformational flexibility of the flap residues are important in the functioning of HIV-1 protease, and must be considered in the future design of drugs against HIV protease and in structure-based drug design in general.
Eur J Biochem 1997 Sep 01
PMID:Structure of HOE/BAY 793 complexed to human immunodeficiency virus (HIV-1) protease in two different crystal forms--structure/function relationship and influence of crystal packing. 934 83

A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.
J Med Chem 1998 Sep 24
PMID:Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold. 974 53

The ability to replace an inhibitor bound to the HIV-1 protease in single crystals with other potent inhibitors offers the possibility of investigating a series of protease inhibitors rapidly and conveniently with the use of X-ray crystallography. This approach affords a fast turnaround of structural information for iterative rational drug designs and obviates the need for studying the complex structures by co-crystallization. The replacement approach has been successfully used with single crystals of the HIV-1 protease complexed with a weak inhibitor. The structures of the complexes obtained by the replacement method are similar to those determined by co-crystallization.
Acta Crystallogr D Biol Crystallogr 1998 Sep 01
PMID:Rapid X-ray diffraction analysis of HIV-1 protease-inhibitor complexes: inhibitor exchange in single crystals of the bound enzyme. 975 36

Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure-based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme-ligand structures, several elastase-inhibitor complexes, the FK506 binding protein, 30 HIV-1 protease-inhibitor complexes, and a number of small and large protein inhibitors. Medium-sized globular proteins typically have 10-20 pockets/cavities. Most often, binding sites are pockets with 1-2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10(2)-10(3)A3. Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is the active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is < or =700 A3, but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C et al., 1994, Nat Struct Biol 1:55-58). Analysis of elastase-inhibitor complexes suggests that CAST can identify ancillary pockets suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SB et al., 1996, Science 274:1531-1534), indicates that CAST pocket computation may provide a priori identification of target proteins for linked-fragment design. CAST analysis of 30 HIV-1 protease-inhibitor complexes shows that the flexible active site pocket can vary over a range of 853-1,566 A3, and that there are two pockets near or adjoining the active site that may be recruited for ligand design.
Protein Sci 1998 Sep
PMID:Anatomy of protein pockets and cavities: measurement of binding site geometry and implications for ligand design. 976 70

Nitric oxide (NO) may modulate the catalytic activity of cysteine-containing enzymes. HIV-1 protease action is modulated by the redox equilibrium of Cys67 and Cys95 regulatory residues. In the present study, the inhibitory effect of NO, released by the NO-donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3), on the aspartyl HIV-1 protease action is reported. HIV-1 protease inactivation via NO-mediated nitrosylation of Cys regulatory residue(s) may represent a possible mechanism for inhibition of HIV-1 replication.
Biochem Biophys Res Commun 1998 Sep 29
PMID:Cysteine nitrosylation inactivates the HIV-1 protease. 978 85

A quantitative structure-activity relationship (QSAR) study is described on some cyclic ureas that inhibit the enzyme HIV-1 protease (HIV-1-PR) and exhibit antiviral potency. Both the enzyme inhibition activity and the antiviral potency were found to be primarily governed by the hydrophobic property of the substituents at the nitrogens (N2/N2') of the urea. Adjacent to the nitrogens, the C1/C1'-substituents are, however, found to affect the activity (inhibition) by their molecular size. The essential binding of the ureas with the receptor is, however, through multiple hydrogen bonding, where the substituents, too, can participate in such binding if they are capable of doing so. A schematic diagram of the overall interaction of the inhibitors with the receptor is presented.
J Enzyme Inhib 1998 Sep
PMID:Quantitative structure-activity relationship studies on cyclic urea-based HIV protease inhibitors. 982 4

NMR and topochemical studies of irreversible HIV-1 protease inhibitors containing a cis-epoxide as amide isostere have been carried out to identify conformational preference of the inhibitors in solution. The inhibitors prefer to adopt extended conformations similar to the beta-strand in solution.
Bioorg Med Chem Lett 1998 Sep 22
PMID:NMR and topochemical studies of peptidomimetic HIV-I protease inhibitors containing a cis-epoxide amide isostere. 987 54

In order to analyze the impact of protease gene polymorphism on response to regimens containing a protease inhibitor, the entire protease coding domain from 58 human immunodeficiency virus type 1 (HIV-1)-infected patients who were protease inhibitor naive was sequenced before therapy was started. Plasma HIV-1 RNA levels were measured at baseline and at month 3 and month 6 after treatment. All patients were treated with a combination of two reverse transcriptase inhibitors and a protease inhibitor (saquinavir EOF [n = 28], ritonavir [n = 16], or indinavir [n = 14]). Before treatment, 30 different positions whose codons differed from the subtype B consensus sequence were observed. Major mutations associated with protease inhibitor resistance were not observed. No statistical correlation between the number of amino acid differences and the treatment efficacy at month 3 (-2.4 log) or month 6 (-2.7 log) was observed. At baseline, genotypic analysis of the HIV-1 protease gene of patients who have never received a protease inhibitor does not allow prediction of the efficacy of regimens containing a protease inhibitor.
J Clin Microbiol 1999 Sep
PMID:Polymorphism of the human immunodeficiency virus type 1 (HIV-1) protease gene and response of HIV-1-infected patients to a protease inhibitor. 1044 74

Better detection of minority human immunodeficiency virus type 1 (HIV-1) populations containing gene mutations may improve the usefulness of antiretroviral resistance testing for clinical management. Molecular cloning of HIV-1 PCR products which might improve minority detection can be slow and difficult, and commercially available recombinant virus assays test drug susceptibility of virus pools. We describe novel plasmids and simple methods for rapid cloning of HIV-1 PCR products from patient specimens and their application to generate infectious recombinant virus clones for virus phenotyping and genotyping. Eight plasmids with differing deletions of sequences encoding HIV-1 protease, reverse transcriptase, or Gag p7/p1 and Gag p1/p6 cleavage sites were constructed for cloning HIV-1 PCR products. A simple HIV-1 sequence-specific uracil deglycosylase-mediated cloning method with the vectors and primers designed here was more rapid than standard ligase-mediated cloning. Pooled and molecularly cloned infectious recombinant viruses were generated with these vectors. Replicative viral fitness and drug susceptibility phenotypes of cloned infectious viruses containing patient specimen-derived sequences were measured. Clonal resistance genotyping analyses were also performed from virus isolates, plasma HIV-1 RNA, and infected cell DNA. Sequencing of a limited number of molecular clones detected minorities of resistant virus not identified in the pooled population PCR product sequence and linkage of minority mutations.
J Clin Microbiol 1999 Sep
PMID:Human immunodeficiency virus type 1 cloning vectors for antiretroviral resistance testing. 1044 80

A structure-based ligand design method is proposed and tested. The method is based on stochastic dynamics simulation of multiple copies of molecular building blocks in the presence of a receptor molecule. The molecular building blocks are assembled into candidate compounds "on the fly" at given intervals during the simulation. In the algorithm, a special effort is made to explore different possible combinations of building blocks and to select an optimum combination. By repeating the cycle of deconstruction and reconstruction in a single simulation, a set of candidate compounds that can be built from the building blocks evolves and is dynamically optimized. The method was tested by breaking two known flexible human immunodeficiency virus type 1 protease inhibitors into building blocks and reassembling them in the active site of the enzyme. For the inhibitor L700417, a set of conformations was generated by the calculation. Among these, the original compound was recovered with the lowest energy at the experimentally observed binding site and in the correct conformation. For pepstatin, the experimentally observed binding mode of the backbone of the inhibitor was reproduced by a calculation in which the building blocks corresponding to the side-chain groups were omitted. Proteins 1999;36:462-470.
Proteins 1999 Sep 01
PMID:Structure-based ligand design by dynamically assembling molecular building blocks at binding site. 1045 88


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