An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives.

Debyser, Zeger; Pauwels, Rudi; Andries, Koen; Desmyter, Jan; Kukla, Michael J.; Janßen, Paul; Clercq, Erik De

doi:10.1073/pnas.88.4.1451

Cited by 154 publications

(93 citation statements)

References 12 publications

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“…0.42 pM, BE= -157 kcal/mol) and nevirapine (ECS0 = 3.41 pM, BE = -78 kcal/mol). The EC5o values, as measured for 8-chloro-TIBO and the dibromo analog of a-APA, are in reasonable agreement with published values for the closely related 9-chloroTIBO (0.7 pM), and dichloro analog of a-APA (0.1 pM), but differ markedly from the literature value for nevirapine (0.084 p M ) (Debyser et al, 1991;Hargrave et al, 1991;Pauwels et al, 1993). At least some of these discrepancies may derive from the fact that substantially different assay conditions were used to obtain the various ECso values.…”

Section: ~~~~~~~supporting

confidence: 78%

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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Section: ~~~~~~~supporting

confidence: 78%

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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“…In previous studies it was found that TIBO and TIBOlike compounds inhibit HIV-1 RT non-competitively with respect to the natural substrate (Debyser et al, 1991;Goldman et al, 1991;Merluzzi et al, 1991). However, for HEPT itself, which is a relatively weak inhibitor of HIV-1 RT, we found a competitive type of inhibition (Debyser et al, 1992a).…”

Section: Discussionmentioning

confidence: 99%

“…The more recently developed dipyridodiazepinones, pyridinones and bis(hetero-aryl)piperazines share this property (Merluzzi et al, 1990;Goldman et al, 1991;Romero et al, 1991). The HIV-l-specific RT inhibitors are ineffective not only against HIV-2 RT, but also against the RTs of avian myeloblastosis virus, Moloney murine leukaemia virus, SIV [from macaques (SlVmac)] and feline leukaemia virus (Merluzzi et al, 1990;Debyser et al, 1991;Goldman et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

“…We have now studied various SIV strains for their susceptibility to inhibition by the novel HIV-l-specific reverse transcriptase (RT) inhibitors tetrahydro-imidazo [4,5, l-jk][ 1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and the 1-(2-hydroxyethoxymethyl)-6-(phenylthio)-thymine (HEPT) derivatives (Pauwels et al, 1990;Baba et al, 1991 ;Debyser et al, 1991). In contrast to the classical RT inhibitors such as phosphonoformic acid (PFA) and 3'-azido-3'-deoxythymidine (AZT) 5'-triphosphate, TIBO and HEPT inhibit HIV-1 RT, but not HIV-2 RT.…”

Section: Introductionmentioning

confidence: 99%

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Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

Debyser

Vreese

Pauwels

et al. 1992

Journal of General Virology

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“…With the discovery of non-nucleoside agents such as HEPT [1] or TIBO [2] (Fig. 1), that are capable of inhibiting this enzyme, a new field has been initiated in anti-AIDS research, revealing a great variety of compounds such as bis(heteroaril)piperazines (BHAPs) [3], TSAO-T [4], or alkenyldiarylmethanes (ADAMs) [5].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles

et al. 1999

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A set of new pyrimido [5,4-b]indole derivatives that are structurally related to some non-nucleoside HIV-1 reverse transcriptase inhibitors were synthesized and biologically evaluated for their activity as inhibitors of wild and mutant HIV-1 RT types in an 'in vitro' recombinant HIV-1 RT screening assay, as well as anti-infectives in HLT4lacZ-1 IIIB cells. Preliminary structure -activity relationships suggest that activity is promoted by simultaneous substitution in positions 2 and 4, especially when chains of alkyldiamine type are present, and by electron-releasing substituents (methoxy) in positions 7 and 8. The inactivity or the very low activity of title derivatives does not suggest interest in AIDS therapy.

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An antiviral target on reverse transcriptase of human immunodeficiency virus type 1 revealed by tetrahydroimidazo-[4,5,1-jk] [1,4]benzodiazepin-2 (1H)-one and -thione derivatives.

Cited by 154 publications

References 12 publications

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

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

Differential inhibitory effects of TIBO derivatives on different strains of simian immunodeficiency virus

Synthesis and anti-HIV-1 activities of new pyrimido[5,4-b]indoles

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