Molecular modelling of humic structures

Ghabbour, Elham A.; Davies, Geoffrey; Bruccoleri, Aldo G.; Sorenson, B. T.; Langford, Cooper H.

doi:10.1039/9781847551085-00193

Cited by 11 publications

(19 citation statements)

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“…Twisting and distortion of quinhydrone complexes are often associated with electron charge transfer type interactions between the complex and a third species. 25,33 Flexibility of NNRTIs appears to be important. It has been proposed that some inhibitors, for example, the DAPY (diarylpyrimidine) inhibitors TMC120 and TMC125, 43 efficiently inhibit the L100I mutant HIV-1 RT because they have torsional flexibility, 11 which allows them to bind effectively to the different conformations of the hydrophobic pocket found in the wild-type HIV-1 RT and the drug-resistant mutants.…”

Section: Designing Flexible Mutation-resistant Nnrtismentioning

confidence: 99%

“…26,[33][34][35] Supramolecular complexes are often able to mimic the spectroscopic behavior of much larger and complex systems. 36 …”

Section: Bruccolerimentioning

confidence: 99%

“…Quinones are ubiquitous in cellular structures and natural systems; they control photosynthetic electron transfer cycles, important redox interactions in cellular processes, and form the redox active and photoactive portion of humic substances, namely fulvic acid and humic acid, found in all soils and natural waters. 26,[30][31][32][33][34][35] Quinonoid dimer complexes intended to be used as HIV-1 RT inhibitors will have varied complexity. In this respect, much may be gleaned from the field of supramolecular chemistry.…”

Section: Designing Flexible Mutation-resistant Nnrtismentioning

confidence: 99%

“…This is because quantum mechanical (QM) methods treat electrons explicitly and such methods are much better suited for chemical species that undergo complex donor-acceptor and noncovalent interactions. 33 However, QM/ MM (quantum mechanical and molecular mechanics) mixed methods may be used to model binding interactions between quinhydrone complexes and the HIV-1 RT enzyme. When dealing with chemical species that are capable of electron donor-acceptor complexes and/or strong noncovalent interactions it is best to use QM/MM mixed methods simultaneously in order to exploit the benefits of both the QM and MM methods.…”

mentioning

confidence: 99%

“…When dealing with chemical species that are capable of electron donor-acceptor complexes and/or strong noncovalent interactions it is best to use QM/MM mixed methods simultaneously in order to exploit the benefits of both the QM and MM methods. 33 Here the region of most interest in the system (i.e., where the NNRTI binding/displacement/bond breaking/forming is taking place in the enzyme, along with selected surrounding catalytically relevant residues) is best treated with a QM method (e.g., semiempirical calculations). The rest of the enzyme may be treated with a MM force field.…”

mentioning

confidence: 99%

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Positional Adaptability in the Design of Mutation-Resistant Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors: A Supramolecular Perspective

Bruccoleri

2013

AIDS Research and Human Retroviruses

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Drug resistance is a key cause of failed treatment of HIV infection. The efficacy of nonnucleoside reverse transcriptase-inhibiting (NNRTI) drugs is impaired by the rapid emergence of drug-resistant mutations. The literature supports the idea that purposefully designed flexible NNRTIs at an active site may help overcome drug resistance. It is proposed here that the usual ''lock and key'' model, with respect to NNRTI drug design, be expanded to consider creating ''master keys'' that would automatically adjust conformations to fit all of the ''locks'' mutations may make. The present work introduces the novel perspective of designing and creating supramolecular assemblies as potential NNRTIs (instead of the relatively more rigid single-molecule inhibitors). Specifically, flexible self-assembling quinhydrone supramolecular dimers formed from quinonoid monomers (designed to be highly flexible NNRTIs themselves) will be offered as a working example of this new perspective in NNRTI drug design. Quinonoid compounds have demonstrated binding interactions at various sites of the HIV-1 RT enzyme, including the elusive ribonuclease H area. Quinhydrone self-organized dimers have at some point in their molecular architecture a noncovalently interacting donor-acceptor ring pair complex. This complex is at the heart of the increased torsional, rotational, and translational motion this species will experience at a particular active site. Flexible supramolecular assemblies, together with their flexible monomer components, may offer a critical advantage in retaining potency against a wide range of drug-resistant HIV-1 RTs. This new supramolecular perspective may also have broader implications in the general field of antimicrobial drug design.

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Section: Designing Flexible Mutation-resistant Nnrtismentioning

confidence: 99%

“…26,[33][34][35] Supramolecular complexes are often able to mimic the spectroscopic behavior of much larger and complex systems. 36 …”

Section: Bruccolerimentioning

confidence: 99%

Section: Designing Flexible Mutation-resistant Nnrtismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Positional Adaptability in the Design of Mutation-Resistant Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors: A Supramolecular Perspective

Bruccoleri

2013

AIDS Research and Human Retroviruses

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Comparison of Laurentian Fulvic Acid luminescence with that of the hydroquinone/quinone model system: Evidence from low temperature fluorescence studies and EPR spectroscopy

Ariese

Assema

Gooijer

et al. 2004

Aquatic Sciences - Research Across Boundaries

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Fluorescence techniques have been used to identify humic substances, (e.g. aquatic fulvic acids from different origins). Synchronous scans have proven adequate for distinguishing detail and differentiating samples. As well, fluorescence has often been used to probe humic interactions with metals and xenobiotic organics. In this study, the fluorescence of a well-characterized material, Laurentian fulvic acid (LFA) was compared with that of a simple hydroquinone/quinone (H 2 Q/Q) model system. Synchronous fluorescence (room T) and laser-excited fluorescence experiments at 10°K were carried out to characterize the fluorophore. The synchronous fluorescence behavior of LFA displayed similarities to that of an equilibrated, aerated, H 2 Q/Q system, but only at higher pH. (Higher pH favours a shift of the redox equilibrium towards quinone.) In contrast, the spectra of LFA suggest the role of "quinone" groups, even at lower pH. A signif- Aquatic Sciencesicant feature of these spectra is a lowest energy band. At low temperature this band was more selectively excited at 470 nm, but vibrationally resolved line narrowed spectra were not observed. Fluorescence lifetimes were very short compared to the laser pulse width of ca. 10 ns. Under the low T condition the spectra of LFA and the model are essentially identical. We suggest that the principal luminophore in LFA is a quinone-hydroquinone type, perhaps a charge transfer complex consistent with the absence of the fluorescence line-narrowing phenomenon. The spectra imply a lowest energy component of LFA emission from a fluorophore very similar to that of the simplest H 2 Q/Q. The significant similarities of the model system to LFA are underscored by striking parallels in the radicals in the two systems seen in well-resolved electron paramagnetic resonance (EPR) spectra that could be obtained at pH = 6.

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Reprint of: Molecular modeling of soil organic matter: Squaring the circle?

Schaumann

Thiele‐Bruhn

2011

Geoderma

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Molecular modelling of humic structures

Cited by 11 publications

References 0 publications

Positional Adaptability in the Design of Mutation-Resistant Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors: A Supramolecular Perspective

Positional Adaptability in the Design of Mutation-Resistant Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors: A Supramolecular Perspective

Comparison of Laurentian Fulvic Acid luminescence with that of the hydroquinone/quinone model system: Evidence from low temperature fluorescence studies and EPR spectroscopy

Reprint of: Molecular modeling of soil organic matter: Squaring the circle?

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