18 research outputs found
Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides
BACKGROUND: Cellulose acetate phthalate (CAP) in soluble form blocks coreceptor binding sites on the virus envelope glycoprotein gp120 and elicits gp41 six-helix bundle formation, processes involved in virus inactivation. CAP is not soluble at pH < 5.5, normal for microbicide target sites. Therefore, the interaction between insoluble micronized CAP and HIV-1 was studied. Carbomer 974P/BufferGel; carrageenan; cellulose sulfate; dextran/dextrin sulfate, poly(napthalene sulfonate) and poly(styrene-4-sulfonate) are also being considered as anti-HIV-1 microbicides, and their antiviral properties were compared with those of CAP. METHODS: Enzyme linked immunosorbent assays (ELISA) were used to (1) study HIV-1 IIIB and BaL binding to micronized CAP; (2) detect virus disintegration; and (3) measure gp41 six-helix bundle formation. Cells containing integrated HIV-1 LTR linked to the β-gal gene and expressing CD4 and coreceptors CXCR4 or CCR5 were used to measure virus infectivity. RESULTS: 1) HIV-1 IIIB and BaL, respectively, effectively bound to micronized CAP. 2) The interaction between HIV-1 and micronized CAP led to: (a) gp41 six-helix bundle formation; (b) virus disintegration and shedding of envelope glycoproteins; and (c) rapid loss of infectivity. Polymers other than CAP, except Carbomer 974P, elicited gp41 six-helix bundle formation in HIV-1 IIIB but only poly(napthalene sulfonate), in addition to CAP, had this effect on HIV-1 BaL. These polymers differed with respect to their virucidal activities, the differences being more pronounced for HIV-1 BaL. CONCLUSIONS: Micronized CAP is the only candidate topical microbicide with the capacity to remove rapidly by adsorption from physiological fluids HIV-1 of both the X4 and R5 biotypes and is likely to prevent virus contact with target cells. The interaction between micronized CAP and HIV-1 leads to rapid virus inactivation. Among other anionic polymers, cellulose sulfate, BufferGel and aryl sulfonates appear most effective in this respect
C-H center dot center dot center dot F Hydrogen Bonds in Solid Solutions of Benzoic Acid and 4-Fluorobenzoic acid
Solid solutions (SS) of benzoic acid (BA) and 4-fluorobenzoic acid (4FBA) are monitored with respect to increasing fluorine content. All 10 SS studied take a crystal structure that is different from the crystal structures of either BA or 4FBA and retain structural uniformity over a wide range of composition. Adoption of a crystal structure different from either of the parent structure types is a unique observation in the context of SS. It implies the influence of directional interactions in the formation of the SS; this idea is strengthened by the observations made in this study. All the structural and interaction parameters monitored follow trends with respect to fluorine content. There is indication of the effect of C-H center dot center dot center dot F hydrogen bonds in the structures
Exploring the structural landscape with `partial' fluoro-substitution as a probe
The landscape of -cinnamic acid is explored by an extension of the previously reported fluorosubstitution protocol. Solid solutions of mono- and difluorocinnamic acids allow for the generation of a large number of experimental data points, which in conjunction with computational crystal structure prediction results can be used to profile the structural landscape of -cinnamic acid. The variation in structure types may be caused by geometrical factors, namely shape-size equivalences, and chemical factors through the intermediacy of weak C-HF hydrogen bonds in the solid solutions
C–H···F Hydrogen Bonds in Solid Solutions of Benzoic Acid and 4‑Fluorobenzoic acid
Solid
solutions (SS) of benzoic acid (BA) and 4-fluorobenzoic acid (4FBA)
are monitored with respect to increasing fluorine content. All 10
SS studied take a crystal structure that is different from the crystal
structures of either BA or 4FBA and retain structural uniformity over
a wide range of composition. Adoption of a crystal structure different
from either of the parent structure types is a unique observation
in the context of SS. It implies the influence of directional interactions
in the formation of the SS; this idea is strengthened by the observations
made in this study. All the structural and interaction parameters
monitored follow trends with respect to fluorine content. There is
indication of the effect of C–H···F hydrogen
bonds in the structures
Six-Component Molecular Solids: ABCD1-(x plus y)ExFy](2)
A strategy has been developed to achieve six-component molecular solids. The first part of the protocol involves the design and development of a family of stoichiometric quaternary cocrystals. It relies on the idea that when a molecule is in two distinct crystallographic environments in a lower-order cocrystal it becomes susceptible to substitution by a new molecule at the site where it is more weakly bound, if it is enthalpically advantageous to do so. Accordingly, a binary cocrystal acts as a stepping stone to a ternary, and so on. However, the subject system ran into a synthetic dead end at the level of quaternary cocrystals, in that no further crystallographic inequivalences could be found. This necessitated the development of the second part of the protocol, which exploits the shape-size similarities of 2-chloro-, 2-bromo-, and 2-methylresorcinols (CRES, BRES, and MRES respectively) and circumvents this synthetic dead end to achieve several five-and six-component solids, wherein the fifth and sixth components are incorporated in a solid solution fashion at the site of the fourth component
Synthon transferability probed with IR spectroscopy: cytosine salts as models for salts of lamivudine
Co-crystal screening of the anti-HIV drug lamivudine was carried out with dicarboxylic acids as co-formers, and three of the resulting crystalline solids, two salts and a co-crystal, were studied with SCXRD, PXRD and FTIR spectroscopy. Salts of cytosine, a molecule that incorporates critical structural features of lamivudine, with the same co-formers, were taken as model systems for IR spectroscopic studies of the synthons in the salts of lamivudine. It is shown that different systems with the same synthon show very similar spectral signatures in the regions corresponding to the synthon absorptions. This reveals again the modular nature of the supramolecular synthon
Designing Ternary Co-crystals with Stacking Interactions and Weak Hydrogen Bonds. 4,4 `-Bis-hydroxyazobenzene
Three ternary co-crystals of the title compound are reported. The design strategy hinges on the identification of a robust synthon with O-H center dot center dot center dot N hydrogen bonds in a binary co-crystal. Construction of this module allows the tuning of pi center dot center dot center dot pi stacking interactions and weak hydrogen bonds to incorporate the third component into the crystal structure. Screening of various co-formers showed that a delicate balance of electrostatics is required for stacking to favor the formation of ternaries. A C-H center dot center dot center dot N hydrogen-bonded motif was also found to occur repetitively in the ternary co-crystals. The directional nature of weak hydrogen bonds allows them to be used effectively in this study
Probing the Crystal Structure Landscape by Doping: 4-Bromo, 4-Chloro, and 4-Methylcinnamic Acids
Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4-bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4-methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4-chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Bratom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl-doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen
MolBridge: a program for identifying nonbonded interactions in small molecules and biomolecular structures
Identification and analysis of nonbonded interactions within a molecule and with the surrounding molecules are an essential part of structural studies, given the importance of these interactions in defining the structure and function of any supramolecular entity. MolBridge is an easy to use algorithm based purely on geometric criteria that can identify all possible nonbonded interactions, such as hydrogen bond, halogen bond, cation-pi, pi-pi and van der Waals, in small molecules as well as biomolecules. The user can either upload three-dimensional coordinate files or enter the molecular ID corresponding to the relevant database. The program is available in a standalone form and as an interactive web server with Jmol and JME incorporated into it. The program is freely downloadable and the web server version is also available at http://nucleix.mbu.iisc.ernet.in/molbridge/index.php
Six-Component Molecular Solids: ABC[D<sub>1–(<i>x</i>+<i>y</i>)</sub>E<sub><i>x</i></sub>F<sub><i>y</i></sub>]<sub>2</sub>
A strategy
has been developed to achieve six-component molecular
solids. The first part of the protocol involves the design and development
of a family of stoichiometric quaternary cocrystals. It relies on
the idea that when a molecule is in two distinct crystallographic
environments in a lower-order cocrystal it becomes susceptible to
substitution by a new molecule at the site where it is more weakly
bound, if it is enthalpically advantageous to do so. Accordingly,
a binary cocrystal acts as a stepping stone to a ternary, and so on.
However, the subject system ran into a synthetic dead end at the level
of quaternary cocrystals, in that no further crystallographic inequivalences
could be found. This necessitated the development of the second part
of the protocol, which exploits the shape-size similarities of 2-chloro-,
2-bromo-, and 2-methylresorcinols (<b>CRES</b>, <b>BRES</b>, and <b>MRES</b> respectively) and circumvents this synthetic
dead end to achieve several five-and six-component solids, wherein
the fifth and sixth components are incorporated in a solid solution
fashion at the site of the fourth component