Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Tintori, Cristina; Esposito, Francesca; Morreale, Francesca; Martini, Riccardo; Tramontano, Enzo; Botta, Maurizio

doi:10.1016/j.bmcl.2015.05.011

Cited by 17 publications

(25 citation statements)

References 29 publications

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“…Among them, kuwanon‐L (Figure A) emerged as the most promising ligand, being characterized by a docking score of −6.48 kcal mol −1 . To enable further study of the binding capabilities of the compounds under investigation toward the sucrose pocket, we also performed a second run of docking studies on a different conformation of the receptor obtained through a previously published (data not shown) molecular dynamics simulation of the sucrose ⋅ IN CCD complex. In detail, the lowest‐energy complex was extracted from the production trajectory.…”

Section: Resultsmentioning

confidence: 99%

“…Starting from such reported structures, we have previously performed molecular dynamic simulations leading to two important results, experimentally validated by biological experiments: 1) sucrose promotes the formation of the IN dimer by increasing the mutual binding free energy of interaction between the two monomers, and 2) sucrose cooperatively acts with Raltegravir and inhibitors of the IN‐LEDGF/p75 protein–protein interaction, enhancing their IN inhibition potency . In this work, pursuing our investigation into the IN sucrose binding site, we applied a structure‐based virtual screening approach to identify ligands that, similarly to sucrose, could establish profitable interactions inside the pocket and, at the same time, determine the binding free energy between the two interacting monomers.…”

Section: Introductionmentioning

confidence: 99%

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Kuwanon‐L as a New Allosteric HIV‐1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation

et al. 2015

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HIV-1 integrase (IN) active site inhibitors are the latest class of drugs approved for HIV treatment. The selection of IN strand-transfer drug-resistant HIV strains in patients supports the development of new agents that are active as allosteric IN inhibitors. Here, a docking-based virtual screening has been applied to a small library of natural ligands to identify new allosteric IN inhibitors that target the sucrose binding pocket. From theoretical studies, kuwanon-L emerged as the most promising binder and was thus selected for biological studies. Biochemical studies showed that kuwanon-L is able to inhibit the HIV-1 IN catalytic activity in the absence and in the presence of LEDGF/p75 protein, the IN dimerization, and the IN/LEDGF binding. Kuwanon-L also inhibited HIV-1 replication in cell cultures. Overall, docking and biochemical results suggest that kuwanon-L binds to an allosteric binding pocket and can be considered an attractive lead for the development of new allosteric IN antiviral agents.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kuwanon‐L as a New Allosteric HIV‐1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation

et al. 2015

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“…The IN-LEDGF/p75 dependent assay allows to measure the inhibition of 3′ processing and strand transfer IN reactions in presence of recombinant LEDGF/p75 protein, as previously described (Tintori et al, 2015). Briefly, 50 nM IN was pre-incubated with increasing concentration of compounds for 1 h at room temperature in reaction buffer containing 20 mM HEPES pH 7.5, 1 mM DTT, 1% glycerol, 20 mM MgCl 2 , 0.05% Brij-35 and 0.1 mg/ml BSA.…”

Section: Methodsmentioning

confidence: 99%

Chelation Motifs Affecting Metal-dependent Viral Enzymes: N′-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

et al. 2017

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Human immunodeficiency virus type 1 (HIV-1) infection, still represent a serious global health emergency. The chronic toxicity derived from the current anti-retroviral therapy limits the prolonged use of several antiretroviral agents, continuously requiring the discovery of new antiviral agents with innovative strategies of action. In particular, the development of single molecules targeting two proteins (dual inhibitors) is one of the current main goals in drug discovery. In this contest, metal-chelating molecules have been extensively explored as potential inhibitors of viral metal-dependent enzymes, resulting in some important classes of antiviral agents. Inhibition of HIV Integrase (IN) is, in this sense, paradigmatic. HIV-1 IN and Reverse Transcriptase-associated Ribonuclease H (RNase H) active sites show structural homologies, with the presence of two Mg(II) cofactors, hence it seems possible to inhibit both enzymes by means of chelating ligands with analogous structural features. Here we present a series of N′-acylhydrazone ligands with groups able to chelate the Mg(II) hard Lewis acid ions in the active sites of both the enzymes, resulting in dual inhibitors with micromolar and even nanomolar activities. The most interesting identified N′-acylhydrazone analog, compound 18, shows dual RNase H-IN inhibition and it is also able to inhibit viral replication in cell-based antiviral assays in the low micromolar range. Computational modeling studies were also conducted to explore the binding attitudes of some model ligands within the active site of both the enzymes.

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“…The INLEDGF/p75-dependent assay allow to measure the inhibition of 3′-processing and strand transfer IN reactions in presence of recombinant LEDGF/p75 protein, as previously described [44]. Briefly, 50 nM IN was pre-incubated with increasing concentration of compounds for 1 h at room temperature in reaction buffer containing 20 mM HEPES pH 7.5, 1 mM DTT, 1% Glycerol, 20 mM MgCl 2 , 0.05% Brij-35 and 0.1 mg/mL BSA.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

Pala

Esposito

Rogolino

et al. 2016

IJMS

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The HIV-1 ribonuclease H (RNase H) function of the reverse transcriptase (RT) enzyme catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate, and represents a suitable target for drug development. A particularly attractive approach is constituted by the interference with the RNase H metal-dependent catalytic activity, which resides in the active site located at the C-terminus p66 subunit of RT. Herein, we report results of an in-house screening campaign that allowed us to identify 4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamides, prepared by the “click chemistry” approach, as novel potential HIV-1 RNase H inhibitors. Three compounds (9d, 10c, and 10d) demonstrated a selective inhibitory activity against the HIV-1 RNase H enzyme at micromolar concentrations. Drug-likeness, predicted by the calculation of a panel of physicochemical and ADME properties, putative binding modes for the active compounds, assessed by computational molecular docking, as well as a mechanistic hypothesis for this novel chemotype are reported.

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Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments

Cited by 17 publications

References 29 publications

Kuwanon‐L as a New Allosteric HIV‐1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation

Kuwanon‐L as a New Allosteric HIV‐1 Integrase Inhibitor: Molecular Modeling and Biological Evaluation

Chelation Motifs Affecting Metal-dependent Viral Enzymes: N′-acylhydrazone Ligands as Dual Target Inhibitors of HIV-1 Integrase and Reverse Transcriptase Ribonuclease H Domain

Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

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