Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template

Kopp, Elizabeth; Miglietta, John; Shrutkowski, Anthony; Shih, Cheng-Kon; Grob, Peter M.; Skoog, Mark T.

doi:10.1093/nar/19.11.3035

Cited by 47 publications

(30 citation statements)

References 13 publications

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“…As observed by Reardon and Miller (1990) and Kopp et at. (1991) the overall efficiency of catalysis, KcatlK m , differed little between homo-and heteropolymeric template-primers (Table 1 and 2). PFA has earlier been reported (Goldman et el., 1991) to displace from HIV-1 RTa compound, L-697,639 and to be mutually exclusive with L-696,229 (Goldman et sl., 1992), both compounds being very similar to L-697,661.…”

Section: Vrang Et El Personal Communication) the Two Mutantsupporting

confidence: 77%

Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

Zhang

Vrang

Unge

et al. 1993

Antivir Chem Chemother

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SummaryTwo mutants of human immunodeficiency virus (HIV) reverse transcriptase (RT), Tyr181 to Cys and Leu100 to lie, have been prepared and characterized by use of various inhibitors. As compared to~~type RT the mutant RT's had lower KeatlK m values. The K m values were lower with heteropolymeric than with homopoIymeric template-primers. Inhibition by phosphonoformate was of mixed type with both wild-type and mutant RT's and the mutants were less sensitive to phosphonoformate than the wild type RT. The nonnucleoside RT inhibitors 9-CI-TIBO and L-697,661 gave a non-competitive inhibition with respect to substrate of the wild type RT. The mutant RT's were inhibited at higher concentrations, showing a mixed type of inhibition with respect to substrate. ddGTP caused a competitive inhibition of wild type and mutant RT's with respect to substrate, RT preparations with different mutations are useful in rapidly characterizing the interaction between various inhibitors and HIV RT and thus facilitate the development of new inhibitors.

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Section: Vrang Et El Personal Communication) the Two Mutantsupporting

confidence: 77%

Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

Zhang

Vrang

Unge

et al. 1993

Antivir Chem Chemother

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“…Inhibitors of HIV-1 RT fall into two categories: the nucleoside and the nonnucleoside reverse transcriptase inhibitors (NNRTIs). The nucleoside RT inhibitors are substrate analogs that act as chain terminators, whereas the NNRTIs are a chemically diverse group of compounds that noncompetitively inhibit DNA polymerization (1)(2)(3).…”

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confidence: 99%

Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors

Pata

Stirtan

Goldstein

et al. 2004

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

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We have determined the crystal structure of the HIV type 1 reverse transcriptase complexed with CP-94,707, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), to 2.8-Å resolution. In addition to inhibiting the wild-type enzyme, this compound inhibits mutant enzymes that are resistant to inhibition by nevirapine, efavirenz, and delaviridine. In contrast to other NNRTI complexes where tyrosines 181 and 188 are pointing toward the enzyme active site, the binding pocket in this complex has the tyrosines pointing the opposite direction, as in the unliganded protein structure, to accommodate CP-94,707. This conformation of the pocket has not been observed previously in NNRTI complexes and substantially alters the shape and surface features that are available for interactions with the inhibitor. One ring of CP-94,707 makes extensive stacking interactions with tryptophan 229, one of the few residues in the NNRTI-binding pocket that cannot readily mutate to give rise to drug resistance. In this conformation of the pocket, mutations of tyrosines 181 and 188 are less likely to disrupt inhibitor binding. Modeling the asparagine mutation of lysine 103 shows that a hydrogen bond between it and tyrosine 188 could form as readily in the CP-94,707 complex as it does in the apoenzyme structure, providing an explanation for the activity of this inhibitor against this clinically important mutant.

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“…I), all of the drugs are highly specific for HIV-I; i.e., they do not inhibit a variety of other DNA polymerases including HIV-RT type 2. Although most of the drugs (such as nevirapine and the TlBO derivatives) appear to be mechanistically noncompetitive for primer, template, and nucleotide (Kopp et al, 1991;Romero et al, 1991), at least one inhibitor (HEPT) has been reported to be competitive with respect to the natural substrate dTTP (Baba et al, 1991). In addition, nonnucleoside inhibitors show a lower cellular toxicity than nucleoside inhibitors (Pauwels et al, 1990; Romero et al, 1991).…”

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confidence: 99%

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

Smith¹,

Hughes²,

Boyer³

et al. 1995

Protein Science

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Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), using crystal coordinate data from a subset of the protein surrounding the binding pocket region,Results from the minimizations of solvated complexes of 2-cyclopropyl-4-methyl-5,l l-dihydro-5H-dipyrido[3,2-b :2',3'-e][ 1,4]diazepin-6-0ne (nevirapine), a-anilino-2, 6-dibromophenylacetamide (a-APA), and 8-chloro-tetrahydro-imidazo(4,5,l-jk)(l,4)-benzodiazepin-2(IH)-thione (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as 7r-electron donors to aromatic side-chain residues surrounding the pocket. However, side-chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these binding energies correlate with EC,, values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. interactions of the inhibitors with individual residues correlate with crystallographic and site-specific mutational data. a-Stacking interactions are important in binding and correlate with drug HOMO RHF/6-31G* energies. Modeling results are discussed with respect to the mechanism of complex formation and the design of nonnucleoside inhibitors that will be more effective against mutants of HIV-1 RT that are resistant to the currently available drugs.

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Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template

Cited by 47 publications

References 13 publications

Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

Characterization of HIV Reverse Transcriptases with Tyr181→Cys and Leu100→lle Mutations

Structure of HIV-1 reverse transcriptase bound to an inhibitor active against mutant reverse transcriptases resistant to other nonnucleoside inhibitors

Molecular modeling studies of HIV‐1 reverse transcriptase nonnucleoside inhibitors: Total energy of complexation as a predictor of drug placement and activity

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