Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations

Durdağı, Serdar; Mavromoustakos, Thomas; Chronakis, Nikos; Παπαδόπουλος, Μάνθος Γ.

doi:10.1016/j.bmc.2008.10.039

Cited by 92 publications

(67 citation statements)

References 33 publications

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“…To alter the hydrophobicity, surface modifications with surface defects and polar groups have been suggested, but these affect the stability of the materials as well as their mechanical and electrical properties (Scida et al 2011). Computational studies of protein-carbon surface interactions have mostly focused on graphene/graphite (Mereghetti & Wade, 2011;Mücksch & Urbassek, 2011;Raffaini & Ganazzoli, 2010;Kang et al 2013;Sun et al 2014b;Yu et al 2012b), CNT (Balamurugan et al 2010;Chen et al 2009b;Tallury & Pasquinelli, 2010;Wang et al 2003) and fullerenes (Durdagi et al 2008;Kraszewski et al 2010;Noon et al 2002).…”

Section: Carbon Allotropesmentioning

confidence: 99%

Modeling and simulation of protein–surface interactions: achievements and challenges

Ozboyaci

Kokh

Corni

et al. 2016

Quart. Rev. Biophys.

197

199

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Abstract. Understanding protein-inorganic surface interactions is central to the rational design of new tools in biomaterial sciences, nanobiotechnology and nanomedicine. Although a significant amount of experimental research on protein adsorption onto solid substrates has been reported, many aspects of the recognition and interaction mechanisms of biomolecules and inorganic surfaces are still unclear. Theoretical modeling and simulations provide complementary approaches for experimental studies, and they have been applied for exploring protein-surface binding mechanisms, the determinants of binding specificity towards different surfaces, as well as the thermodynamics and kinetics of adsorption. Although the general computational approaches employed to study the dynamics of proteins and materials are similar, the models and force-fields (FFs) used for describing the physical properties and interactions of material surfaces and biological molecules differ. In particular, FF and water models designed for use in biomolecular simulations are often not directly transferable to surface simulations and vice versa. The adsorption events span a wide range of time-and length-scales that vary from nanoseconds to days, and from nanometers to micrometers, respectively, rendering the use of multi-scale approaches unavoidable. Further, changes in the atomic structure of material surfaces that can lead to surface reconstruction, and in the structure of proteins that can result in complete denaturation of the adsorbed molecules, can create many intermediate structural and energetic states that complicate sampling. In this review, we address the challenges posed to theoretical and computational methods in achieving accurate descriptions of the physical, chemical and mechanical properties of protein-surface systems. In this context, we discuss the applicability of different modeling and simulation techniques ranging from quantum mechanics through all-atom molecular mechanics to coarse-grained approaches. We examine uses of different sampling methods, as well as free energy calculations. Furthermore, we review computational studies of protein-surface interactions and discuss the successes and limitations of current approaches.

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Section: Carbon Allotropesmentioning

confidence: 99%

Modeling and simulation of protein–surface interactions: achievements and challenges

Ozboyaci

Kokh

Corni

et al. 2016

Quart. Rev. Biophys.

197

199

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“…Since the original report, it has been assumed that the anti-HIV activity of fullerene derivatives is mediated mainly, if not exclusively, by inhibition of the viral protease. Evidence supporting this mechanism is based mostly on molecular docking simulations that predict the binding of these compounds to the active site of HIV-1 protease due to their size and conformational complementarity (11,13,(19)(20)(21). However, this model lacks support from empirical data.…”

mentioning

confidence: 99%

Fullerene Derivatives Strongly Inhibit HIV-1 Replication by Affecting Virus Maturation without Impairing Protease Activity

Martinez

Castro

Seong

et al. 2016

Antimicrob Agents Chemother

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Three compounds (1, 2, and 3) previously reported to inhibit HIV-1 replication and/or in vitro activity of reverse transcriptase were studied, but only fullerene derivatives 1 and 2 showed strong antiviral activity on the replication of HIV-1 in human CD4 ؉ T cells. However, these compounds did not inhibit infection by single-round infection vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped viruses, indicating no effect on the early steps of the viral life cycle. In contrast, analysis of single-round infection VSV-G-pseudotyped HIV-1 produced in the presence of compound 1 or 2 showed a complete lack of infectivity in human CD4؉ T cells, suggesting that the late stages of the HIV-1 life cycle were affected. Quantification of virion-associated viral RNA and p24 indicates that RNA packaging and viral production were unremarkable in these viruses. However, Gag and Gag-Pol processing was affected, as evidenced by immunoblot analysis with an anti-p24 antibody and the measurement of virion-associated reverse transcriptase activity, ratifying the effect of the fullerene derivatives on virion maturation of the HIV-1 life cycle. Surprisingly, fullerenes 1 and 2 did not inhibit HIV-1 protease in an in vitro assay at the doses that potently blocked viral infectivity, suggesting a protease-independent mechanism of action. Highlighting the potential therapeutic relevance of fullerene derivatives, these compounds block infection by HIV-1 resistant to protease and maturation inhibitors.

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“…In this case, we calculated the binding affinities according to the formula ΔG = −RTlnK i, [44]. We adapted the working hypothesis introduced by Durdagi et al, Naik et al and Conn et al that assume that K i is equal to the IC 50 [μM] [45][46][47].…”

Section: Docking Results For Pm7 Optimized Geometriesmentioning

confidence: 99%

Geometry optimization of steroid sulfatase inhibitors - the influence on the free binding energy with STS

et al. 2017

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In the paper we review the application of two techniques (molecular mechanics and quantum mechanics) to study the influence of geometry optimization of the steroid sulfatase inhibitors on the values of descriptors coded their chemical structure and their free binding energy with the STS protein. We selected 22 STS-inhibitors and compared their structures optimized with MM+, PM7 and DFT B3LYP/6-31++G* approaches considering separately the bond lengths, angles, dihedral angles and total energies. We proved that different minimum energy conformers could be generated depending on the choice of the optimization method. However, the results indicated that selection of the geometry optimization method did not affect the optimal STS inhibitor coordinates, and hence the values of molecular descriptors which describe the 3D structure of the molecule. To study the interaction pattern of the STS inhibitors (optimized using different methods) with the target receptor we applied two strategies: AutoDock and PathDock. The docking studies point out that selection of software to docking simulation is one of the crucial factors determining the binding mode of STS inhibitors with their molecular target. Other factor is related to the ligand orientation in the binding pocket. Finally, obtained results indicate that MM+ and PM7 methods (faster and less expensive) could be successfully employed to geometry optimization of the STS inhibitors before their docking procedure as well as for molecular descriptors calculations.

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Computational design of novel fullerene analogues as potential HIV-1 PR inhibitors: Analysis of the binding interactions between fullerene inhibitors and HIV-1 PR residues using 3D QSAR, molecular docking and molecular dynamics simulations

Cited by 92 publications

References 33 publications

Modeling and simulation of protein–surface interactions: achievements and challenges

Modeling and simulation of protein–surface interactions: achievements and challenges

Fullerene Derivatives Strongly Inhibit HIV-1 Replication by Affecting Virus Maturation without Impairing Protease Activity

Geometry optimization of steroid sulfatase inhibitors - the influence on the free binding energy with STS

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