In vitro and in silico investigation of interferonogenic analogues of nucleic acids, artificially programmed to block the initial stages of HIV infection of cells
“…Among the possible alicyclic structures the dNb species and their dislocation in side positions of polyanionic chain was selected by in vitro screening [3–10] in search for most anti-HIV-1 active synthetic polymers of the series I followed by the docking-based analysis [9, 16] (Fig. 3, for example).…”
Section: Resultsmentioning
confidence: 99%
“…Within this series of polymers the alternating cyclocopolymers of divinyl ether with maleic acid/their salt (see Scheme 1, formula I) possess the amplified anti-HIV activity [9], when the side groups (X = OH/ONa) are partially (optimally, the 6–8 % of total amount of the X-groups) substituted by the cage-type anchors ( Anc ).Scheme 1The observable synthetic polymers. An —Anionic side groups; Anc —pendant anchors derived from hydrophobic alicycles: adamantane ( Ad ), norbornane ( Nb ), norbornen ( Nb
= ), epoxynorbornane ( Nb
O ), dinobornene ( dNb )—i.e., tetracyclo-[4.4.0.1 2.5 1 7.10 ]-dodecene, etc.…”
Section: Introductionmentioning
confidence: 99%
“…The docking was performed recently in terms of newly formulated algorithm for step-by-step approximation from fragments of polymeric backbone and side-groups toward real polymeric chains [9, 16]. Among sub-domains of the gp41 ectodomain (Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Just such tendency to polyvalent binding has been discovered by the docking pre-study of the polymers I in connection with the [HR1] 3 complex [9, 16]. …”
In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands–target interactions. Some newly MD-discovered aspects of the ligand’s backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-014-9749-8) contains supplementary material, which is available to authorized users.
“…Among the possible alicyclic structures the dNb species and their dislocation in side positions of polyanionic chain was selected by in vitro screening [3–10] in search for most anti-HIV-1 active synthetic polymers of the series I followed by the docking-based analysis [9, 16] (Fig. 3, for example).…”
Section: Resultsmentioning
confidence: 99%
“…Within this series of polymers the alternating cyclocopolymers of divinyl ether with maleic acid/their salt (see Scheme 1, formula I) possess the amplified anti-HIV activity [9], when the side groups (X = OH/ONa) are partially (optimally, the 6–8 % of total amount of the X-groups) substituted by the cage-type anchors ( Anc ).Scheme 1The observable synthetic polymers. An —Anionic side groups; Anc —pendant anchors derived from hydrophobic alicycles: adamantane ( Ad ), norbornane ( Nb ), norbornen ( Nb
= ), epoxynorbornane ( Nb
O ), dinobornene ( dNb )—i.e., tetracyclo-[4.4.0.1 2.5 1 7.10 ]-dodecene, etc.…”
Section: Introductionmentioning
confidence: 99%
“…The docking was performed recently in terms of newly formulated algorithm for step-by-step approximation from fragments of polymeric backbone and side-groups toward real polymeric chains [9, 16]. Among sub-domains of the gp41 ectodomain (Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Just such tendency to polyvalent binding has been discovered by the docking pre-study of the polymers I in connection with the [HR1] 3 complex [9, 16]. …”
In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands–target interactions. Some newly MD-discovered aspects of the ligand’s backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.Electronic supplementary materialThe online version of this article (doi:10.1007/s10822-014-9749-8) contains supplementary material, which is available to authorized users.
“…with broad spectrum of biomedical applicability . Authors of the paper have their own background in design, synthesis, and development of DVEMAN‐derived inhibitors of HIV, influenza, herpes, and other human viruses …”
Products of free‐radical polymerization (FRP) are usually not regulated on the molecular scale, consisting of blocks obtained through the fastest kinetic scheme pathways. The side or kinetically restricted products can be a source of impurities in a complex FRP case, or possess new properties if isolated solely. FRP synthesis of poly(divinyl ether‐alt‐maleic anhydride), known as “DIVEMA”, serves as a polymerization example with such kinetic and thermodynamic complexities. Uncertainty in factors regulating polymer structure is a challenge in advancement “DIVEMA” derivatives toward medical practice. In‐depth investigation via quantum‐chemical and molecular mechanics methods unveils mechanistic aspects of polymer stereoisomerism and confirms possible isolation of thermodynamically or kinetically controlled products on a large data set. Strategies toward regulation of 5‐exo/6‐endo cycloisomerism are theorized and then studied via microkinetic modeling. Thermodynamically controlled products can be isolated utilizing lower monomer concentrations, in range of 10−3 to 10−1 m, and/or application of a complexing agent that is better to realize via solvents, capable of formation π‐ and σ‐radical complexes. Change of electrophilic monomer is proposed as an approach for designing more molecularscale adjustable copolymerization processes. Methodology, obtained results, and conclusions for “DIVEMA” can be valuable to control other FRP processes on the molecular scale, unlocking polymers with improved or new functionalities.
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