Effects of Drug Resistance Mutations L100I and V106A on the Binding of Pyrrolobenzoxazepinone Nonnucleoside Inhibitors to the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Catalytic Complex

Locatelli, Giada A.; Campiani, Giuseppe; Cancio, Reynel; Morelli, Elena; Ramunno, Anna; Gemma, Sandra; Hübscher, Ulrich; Spadari, Silvio; Maga, Giovanni

doi:10.1128/aac.48.5.1570-1580.2004

Cited by 6 publications

(6 citation statements)

References 37 publications

(47 reference statements)

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“…In previous studies of resistance mutations of another enzyme of HIV, reverse transcriptase, G was considered to approximate changes in IC 50 [44][45][46]. This is at odds with the fact that the majority of the mutations for which this approximation was used, such as L100I, V106A, and Y188L, although not located directly in the active site, have been previously reported to affect the catalytic potential of the enzyme [47][48][49][50][51]. Although some studies show correlation between predicted relative drug binding free energy upon HIV protease mutation and the one approximated by IC 50 measurements [52], RAMs affecting the catalytic activity of protease have also been reported [39,40,53,54].…”

Section: Estimation Of Resistance Factors From the Change In The Inhimentioning

confidence: 99%

Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors

et al. 2020

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Background: HIV-1 can develop resistance to antiretroviral drugs, mainly through mutations within the target regions of the drugs. In HIV-1 protease, a majority of resistance-associated mutations that develop in response to therapy with protease inhibitors are found in the protease's active site that serves also as a binding pocket for the protease inhibitors, thus directly impacting the protease-inhibitor interactions. Some resistance-associated mutations, however, are found in more distant regions, and the exact mechanisms how these mutations affect protease-inhibitor interactions are unclear. Furthermore, some of these mutations, e.g. N88S and L76V, do not only induce resistance to the currently administered drugs, but contrarily induce sensitivity towards other drugs. In this study, mutations N88S and L76V, along with three other resistance-associated mutations, M46I, I50L, and I84V, are analysed by means of molecular dynamics simulations to investigate their role in complexes of the protease with different inhibitors and in different background sequence contexts. Results: Using these simulations for alchemical calculations to estimate the effects of mutations M46I, I50L, I84V, N88S, and L76V on binding free energies shows they are in general in line with the mutations' effect on IC 50 values. For the primary mutation L76V, however, the presence of a background mutation M46I in our analysis influences whether the unfavourable effect of L76V on inhibitor binding is sufficient to outweigh the accompanying reduction in catalytic activity of the protease. Finally, we show that L76V and N88S changes the hydrogen bond stability of these residues with residues D30/K45 and D30/T31/T74, respectively. Conclusions: We demonstrate that estimating the effect of both binding pocket and distant mutations on inhibitor binding free energy using alchemical calculations can reproduce their effect on the experimentally measured IC 50 values. We show that distant site mutations L76V and N88S affect the hydrogen bond network in the protease's active site, which offers an explanation for the indirect effect of these mutations on inhibitor binding. This work thus provides valuable insights on interplay between primary and background mutations and mechanisms how they affect inhibitor binding.

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Section: Estimation Of Resistance Factors From the Change In The Inhimentioning

confidence: 99%

Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors

et al. 2020

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“…In previous studies of resistance mutations of another enzyme of HIV, reverse transcriptase, ∆∆G was considered to approximate changes in IC 50 [44,45,46]. This is at odds with the fact that the majority of the mutations for which this approximation was used, such as L100I, V106A, and Y188L, although not located directly in the active site, have been previously reported to affect the catalytic potential of the enzyme [47,48,49,50,51]. Although some studies show correlation between predicted relative drug binding free energy upon HIV protease mutation and the one approximated by IC 50 measurements [52], RAMs affecting the catalytic activity of protease have also been reported [53,39,40,54].…”

Section: Estimation Of Resistance Factors From the Change In The Inhimentioning

confidence: 99%

Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitisation Towards Protease Inhibitors

Bastys

Gapsys

Walter

et al. 2020

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Background HIV-1 can develop resistance to antiretroviral drugs, mainly through mutations within the target regions of the drugs. In HIV-1 protease, a majority of resistance-associated mutations that develop in response to therapy with protease inhibitors are found in the protease’s active site that serves also as a binding pocket for the protease inhibitors, thus directly impacting the protease-inhibitor interactions. Some resistance-associated mutations, however, are found in more distant regions, and the exact mechanisms how these mutations affect protease-inhibitor interactions are unclear. Furthermore, some of these mutations, e.g. N88S and L76V, do not only induce resistance to the currently administered drugs, but contrarily induce sensitivity towards other drugs. In this study, mutations N88S and L76V, along with three other resistance-associated mutations, M46I, I50L, and I84V, are analysed by means of molecular dynamics simulations to investigate their role in complexes of the protease with different inhibitors and in different background sequence contexts. Results Using these simulations for alchemical calculations to estimate the effects of mutations M46I, I50L, I84V, N88S, and L76V on binding free energies shows they are in general in line with the mutations’ effect on IC50 values. For the primary mutation L76V, however, the presence of a background mutation M46I in our analysis influences whether the unfavourable effect of L76V on inhibitor binding is sufficient to outweigh the accompanying reduction in catalytic activity of the protease. Finally, we show that L76V and N88S changes the hydrogen bond stability of these residues with residues D30/K45 and D30/T31/T74, respectively. Conclusions We demonstrate that estimating the effect of both binding pocket and distant mutations on inhibitor binding free energy using alchemical calculations can reproduce their effect on the experimentally measured IC50 values. We show that distant site mutations L76V and N88S affect the hydrogen bond network in the protease’s active site, which offers an explanation for the indirect effect of these mutations on inhibitor binding. This work thus provides valuable insights on interplay between primary and background mutations and mechanisms how they affect inhibitor binding.

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“…For this compound, a significant antiviral efficacy was combined to a limited spectrum of activity. 7 Later on, a thorough exploitation of structure-activity relationship (SAR) trends, aimed at the discovery of more potent and broadspectrum NNRTIs allowed us the identification of a novel class 1-2, Table 1 of the Supporting Information (SI), and Figures 1-3). A stereoselective interaction of the pure enantiomers with the HIV-1 RT, which also correlates with cellular assays, was demonstrated and rationalized through a molecular modeling study.…”

Section: Introductionmentioning

confidence: 99%

Specific Targeting of Highly Conserved Residues in the HIV-1 Reverse Transcriptase Primer Grip Region. 2. Stereoselective Interaction to Overcome the Effects of Drug Resistant Mutations

et al. 2009

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Starting from the prototypic compound 4, we describe new, potent, and broad-spectrum pyrrolobenzo(pyrido)oxazepinones antivirals. A biochemical and enzymological investigation was performed for defining their mechanism of inhibition at either recombinant HIV-1 RT wild type and non-nucleoside reverse transcriptase inhibitors (NNRTIs)-resistant mutants. For the novel compounds (S)-(+)-5 and (S)-(-)-7, a clear-cut stereoselective mechanism of enzyme inhibition was found. Molecular modeling studies were performed for revealing the underpinnings of this behavior.

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Effects of Drug Resistance Mutations L100I and V106A on the Binding of Pyrrolobenzoxazepinone Nonnucleoside Inhibitors to the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Catalytic Complex

Cited by 6 publications

References 37 publications

Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors

Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors

Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitisation Towards Protease Inhibitors

Specific Targeting of Highly Conserved Residues in the HIV-1 Reverse Transcriptase Primer Grip Region. 2. Stereoselective Interaction to Overcome the Effects of Drug Resistant Mutations

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