Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule

Lucca, George V. De; Erickson‐Viitanen, Susan; Lam, Patrick Y.S.

doi:10.1016/s1359-6446(96)10048-9

Cited by 67 publications

(44 citation statements)

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“…Displacing a conformationally restrained water increases the entropy of the system, and direct interaction with the flaps may help to stabilize the closed state of the protease. Many other cyclic compounds now displace the structural water (15)(16)(17)(18).…”

Section: Discussionmentioning

confidence: 99%

“…The cyclic urea (CU) scaffold is therefore well suited to interact with the viral protease and to discriminate against human proteases. Since these inhibitors were first reported, the number of CU mimics has rapidly increased, and this class of cyclic compounds may soon become a viable alternative to the currently available antiretroviral agents (15)(16)(17)(18). In a continuing effort to identify new interactions that might increase the potency of our inhibitors, and other members of the cyclic family, we have performed a structural analysis of HIV-1 protease in complex with a series of CUs, which have IC 90 (concentration of inhibitor required to inhibit viral replication by 95%) values ranging from 5.1 to 4700 nM.…”

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confidence: 99%

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Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

DeLoskey

Huston

et al. 1998

Journal of Biological Chemistry

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As long as the threat of human immunodeficiency virus (HIV) protease drug resistance still exists, there will be a need for more potent antiretroviral agents. We have therefore determined the crystal structures of HIV-1 protease in complex with six cyclic urea inhibitors: XK216, XK263, DMP323, DMP450, XV638, and SD146, in an attempt to identify 1) the key interactions responsible for their high potency and 2) new interactions that might improve their therapeutic benefit. The structures reveal that the preorganized, C 2 symmetric scaffolds of the inhibitors are anchored in the active site of the protease by six hydrogen bonds and that their P1 and P2 substituents participate in extensive van der Waals interactions and hydrogen bonds. Because all of our inhibitors possess benzyl groups at P1 and P1, their relative binding affinities are modulated by the extent of their P2 interactions, e.g. XK216, the least potent inhibitor (K i (inhibition constant) ‫؍‬ 4.70 nM), possesses the smallest P2 and the lowest number of P2-S2 interactions; whereas SD146, the most potent inhibitor (K i ‫؍‬ 0.02 nM), contains a benzimidazolylbenzamide at P2 and participates in fourteen hydrogen bonds and ϳ200 van der Waals interactions. This analysis identifies the strongest interactions between the protease and the inhibitors, suggests ways to improve potency by building into the S2 subsite, and reveals how conformational changes and unique features of the viral protease increase the binding affinity of HIV protease inhibitors.An essential step in the life cycle of the human immunodeficiency virus (HIV) 1 is the proteolytic cleavage of the viral polyprotein gene products of gag and gag-pol into active structural and replicative proteins (1, 2). The finding that a viralencoded protease is responsible for processing these precursors, and that its inactivation produces immature, noninfectious viral particles, elicited an intense search for synthetic inhibitors. The first competitive inhibitors of HIV protease (PR) were transition-state analogs (peptidomimetics) in which the scissile bonds were replaced with nonhydrolyzable isosteres such as a reduced amide, phosphinate, hydroxyethylene, dihydroxyethylene, statine, and hydroxyethylamine (3-5). Recently, the Food and Drug Administration (FDA) has approved the use of four peptidomimetic protease inhibitors (saquinavir, ritonavir, indinavir, and nelfinavir) to treat HIV infection. Although these compounds are potent inhibitors of the wild-type protease, their therapeutic benefit is, in most cases, short-lived because they select for variants of HIV that have a reduced sensitivity toward inhibitors, as a result of mutations within the HIV protease sequence (6 -10). In an attempt to delay the onset of drug resistance, the FDA approved the use of combination therapy, i.e. a mixture of protease and reverse transcriptase antiretroviral agents. Although multidrug therapy has reduced the plasma viral load of some HIV-infected individuals to undetectable levels (11), the daunting ability of the virus...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

DeLoskey

Huston

et al. 1998

Journal of Biological Chemistry

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“…However, the efficacy of inhibition by the more potent inhibitors 11 and 12 was progressively increased up to 5-fold in mutant enzymes. Overall, these results provide new insights into the specificity (35) and resistance development (36,37) of the aspartyl proteases and may help development of new inhibitors that are better than those currently available (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

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confidence: 90%

“…Although several competitive inhibitors of this protease have been approved or are in clinical trials (1)(2)(3)(4)(5)(6)(7)(8)(9), many drugresistant mutant HIV PRs have been identified (10,11). In addition, the drug development process has been relatively slow because of the lack of animal systems to test the effectiveness of the inhibitors.…”

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confidence: 99%

Analysis of the S3 and S3′ subsite specificities of feline immunodeficiency virus (FIV) protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo

Lee

Laco

Torbett

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

112

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The S3 and S3 subsite binding specificities of HIV and feline immunodeficiency virus proteases (FIV) proteases (PRs) have been explored by using C 2 -symmetric competitive inhibitors. The inhibitors evaluated contained (1S, 2R, 3R, 4S)-1,4-diamino-1,4-dibenzyl-2,3-diol as P1 and P1 units, Val as P2 and P2 residues, and a variety of amino acids at the P3 and P3 positions. All inhibitors showed very high potency against HIV PR in vitro, and their K i values ranged between 1.1 and 2.6 nM. In contrast to the low restriction of P3 and P3 residues observed in HIV PR, FIV PR exhibited strong preference for small hydrophobic groups at the S3 and S3 subsites. Within this series, the most effective inhibitor against FIV PR contained Ala at P3 and P3. Its K i of 41 nM was 415-and 170-fold lower than those of the inhibitors without the P3 and P3 moieties or with the Phe at these positions, respectively. In addition, these compounds were tested against mutant FIV PRs, which contain amino acid substitutions corresponding to those in native HIV PR at homologous sites, and their efficacy of inhibition progressively increased up to 5-fold. The most potent FIV PR inhibitor was selected for examination of its effectiveness in tissue culture, and it was able to block nearly 100% of virus production in an acute infection at 1 g͞ml (1.1 M) against HIV, FIV, and simian immunodeficiency virus. Furthermore, it was not toxic to cells, and even after 2 months of culture there was no sign of resistance development by virus. The findings suggest that inhibitors with small P3 residue may be efficacious against a broad range of HIV variants as well as interspecies PRs.

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“…The carbonic anhydrase inhibitor and anti-glaucoma drug dorzolamide was the first drug approved for clinical use that was developed by computer-aided drug design. This was rapidly followed by HIV protease inhibitors (De Lucca et al 1997;Greer et al 1994) and the cancer chemotherapeutic agent and tyrosine kinase inhibitor, imatinib (gleevec) (Druker and Lydon 2000). Current drugs developed by computer-aided drug design target 5-HT3 and acetylcholine receptor agonists, Gprotein coupled receptors such as CCR5 and NK1, proton pumps and TRP channels.…”

Section: Current Successes and Future Directionsmentioning

confidence: 99%

Polypeptide and Protein Modeling for Drug Design

O’Mara

Deplazes

2013

Encyclopedia of Computational Neuroscience

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Computational modeling, structure-aided drug design, computational structural biology DefinitionModeling of polypeptides and proteins, often referred to as biomolecular or molecular modeling, encompasses the use of theoretical models and computational methods to model the structure and dynamics of molecules of biological interest such as peptides, proteins and small organic molecules (ligands).The aims of protein and peptide modeling for drug design include: (i) modeling the threedimensional structure of proteins of current or potential drug targets; (ii) identifying and characterizing the structural dynamics associated with the function of a particular protein or peptide; and (iii) predicting the structure and molecular interactions of protein-ligand complexes. This knowledge underpins structure-based and rational drug design. It can aid in the design and optimization of drug molecules by shedding light on their mode of action, specificity and selectivity.

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Cyclic HIV protease inhibitors capable of displacing the active site structural water molecule

Cited by 67 publications

References 82 publications

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors

Analysis of the S3 and S3′ subsite specificities of feline immunodeficiency virus (FIV) protease: Development of a broad-based protease inhibitor efficacious against FIV, SIV, and HIV in vitro and ex vivo

Polypeptide and Protein Modeling for Drug Design

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