Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme

Kim, E. E.; Baker, Christopher T. H.; Dwyer, M.D.; Murcko, Mark A.; Rao, B. Govinda; Tung, Roger D.; Navia, Manuel A.

doi:10.1021/ja00108a056

Cited by 409 publications

(304 citation statements)

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“…1b). In contrast, the shapes of the five commercially available drugs, as observed in the wild-type complexes (7,(23)(24)(25)55) do not form this toroid (Fig. 1d).…”

Section: Resultsmentioning

confidence: 89%

“…Structure solution and crystallographic refinement for all five structures were carried out using the Crystallography & NMR System version 0.9 (5). A previously published inhibitor complex (PDB:1MTR) (35) [25]), IDV (1HSG [7]), NFV (1OHR [23]), SQV (1HXB [55]), and RTV (1HXW [24]). (c and d) Consensus volume occupied by the three substrates (c) and the five inhibitors (d), generated using GRASP (40).…”

Section: Methodsmentioning

confidence: 99%

“…We conducted structural analysis using these complexes in relevance to ligand-protease interaction, which includes shape complementarity, hydrogen bonds, van der Waals (VDW) packing, and estimation of VDW interaction energy. Since the wild-type structures for these ligands are already available in the Protein Data Bank (7,(23)(24)(25)55), it allowed us to make a direct structural comparison. The findings of this study suggest that Val82 is not crucial for substrate recognition but is critical for inhibitor binding.…”

mentioning

confidence: 99%

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Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

Prabu-Jeyabalan

Nalivaika

King

et al. 2003

J Virol

102

121

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Under the selective pressure of protease inhibitor therapy, patients infected with human immunodeficiency virus (HIV) often develop drug-resistant HIV strains. One of the first drug-resistant mutations to arise in the protease, particularly in patients receiving indinavir or ritonavir treatment, is V82A, which compromises the binding of these and other inhibitors but allows the virus to remain viable. To probe this drug resistance, we solved the crystal structures of three natural substrates and two commercial drugs in complex with an inactive drug-resistant mutant (D25N/V82A) HIV-1 protease. Through structural analysis and comparison of the protein-ligand interactions, we found that Val82 interacts more closely with the drugs than with the natural substrate peptides. The V82A mutation compromises these interactions with the drugs while not greatly affecting the substrate interactions, which is consistent with previously published kinetic data. Coupled with our earlier observations, these findings suggest that future inhibitor design may reduce the probability of the appearance of drug-resistant mutations by targeting residues that are essential for substrate recognition.

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“…1b). In contrast, the shapes of the five commercially available drugs, as observed in the wild-type complexes (7,(23)(24)(25)55) do not form this toroid (Fig. 1d).…”

Section: Resultsmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

Prabu-Jeyabalan

Nalivaika

King

et al. 2003

J Virol

102

121

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“…One such compound, 3-hydroxyg-butyrolactone (3HBL), is widely used in the pharmaceutical industry as a chiral building block for the statin class of cholesterol-reducing drugs such as Crestor and Lipitor, as well as the antibiotic Zyvox, and the antihyperlipidemic medication Zetia 3 . Other pharmaceuticals derived from 3HBL include HIV inhibitors 4 and the nutritional supplement L-carnitine 5 . 3HBL can readily be transformed into a variety of three-carbon building blocks 6 and has been listed as one of the top value-added chemicals from biomass by the US Department of Energy 7 .…”

mentioning

confidence: 99%

A platform pathway for production of 3-hydroxyacids provides a biosynthetic route to 3-hydroxy-γ-butyrolactone

et al. 2013

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The replacement of petroleum feedstocks with biomass to produce platform chemicals requires the development of appropriate conversion technologies. 3-Hydroxy-g-butyrolactone has been identified as one such chemical; however, there are no naturally occurring biosynthetic pathways for this molecule or its hydrolyzed form, 3,4-dihydroxybutyric acid. Here we design a novel pathway to produce various chiral 3-hydroxyacids, including 3,4-dihydroxybutyric acid, consisting of enzymes that condense two acyl-CoAs, stereospecifically reduce the resulting b-ketone and hydrolyze the CoA thioester to release the free acid. Acetyl-CoA serves as one substrate for the condensation reaction, whereas the second is produced intracellularly by a pathway enzyme that converts exogenously supplied organic acids. Feeding of butyrate, isobutyrate and glycolate results in the production of 3-hydroxyhexanoate, 3-hydroxy-4-methylvalerate and 3,4-dihydroxybutyric acid þ 3-hydroxy-gbutyrolactone, respectively, molecules with potential uses in applications from materials to medicines. We also unexpectedly observe the condensation reaction resulting in the production of the 2,3-dihydroxybutyric acid isomer, a potential value-added monomer.

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“…A structure-assisted drug design effort by Murcko and coworkers including FEP calculations contributed towards the discovery of the FDA-approved PR inhibitor amprenavir (formerly VX-478) [83][84][85]. Additional successful applications of the FEP method for the calculation of HIV-1 PR inhibition, including non-peptide inhibitors, have been reported by McCarrick and Kollman [86], Rao and Murcko [87], Varney et al [88], Chen and Tropsha [89], and Wang et al [90] and has laid the path for more recent accomplishments in FEP guided design of HIV-1 reverse transcriptase inhibitors.…”

Section: Hiv-1 Prmentioning

confidence: 99%

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Acevedo¹,

Ambrose²,

Flaherty³

et al. 2012

curr drug metab

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Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

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Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme

Cited by 409 publications

References 0 publications

Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

Viability of a Drug-Resistant Human Immunodeficiency Virus Type 1 Protease Variant: Structural Insights for Better Antiviral Therapy

A platform pathway for production of 3-hydroxyacids provides a biosynthetic route to 3-hydroxy-γ-butyrolactone

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

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