1,720,977 research outputs found
On the interplay among non-covalent interactions and activity of 4-aminoquinoline antimalarials: a crystallographic and spectroscopic study
Full text linkMalaria is due to protozoa of the genus Plasmodium, which infect human red blood cells and digest the host hemoglobin. Degradation of the latter in the acidic food vacuole (pH ~ 5) releases free hematin (hydroxylated Fe protoporphyrin-IX, FePPIX(OH)), which is toxic to the parasite [1]. Therefore, Plasmodium deactivates hematin by promoting its crystallization into harmless pale yellow P1bar crystals of beta-hematin. 4-aminoquinoline drugs (AQ), such as chloroquine (CQ) and piperaquine (PQ), interfere with this detoxification process, either by coordinating free heme in solution [2], or by poisoning fastest-growing crystal faces of beta-hematin [3]. However, there is no general consensus on the structure of the AQ/heme complex [4], which depends on various chemical variables (aqueous/lipidic environment, pH).
We here aim at quantitatively disclosing the chemical physics underlying the pharmacophoric features of CQ and PQ in the context of predicting which chemical modifications should be applied on the AQ scaffold to enhance the drug functionality against the biochemical resistance mechanism evolved by Plasmodium [5,6].
EXAFS spectroscopy in solution across the Fe Kalpha absorption edge (~ 7.1 keV) explored the first shell coordination geometry of iron in hematin, both in the presence and in the absence of AQ systems. Differences in the signal were related to the possible occurrence of a direct Fe–N coordinative bond involving the quinoline nitrogen atom, which might coexist with other possible (e.g. pi···pi stacked) adduct geometries [5] (Fig. 1). Quantum mechanical DFT calculations showed that an aliphatic tertiary NH+ amino group might also be a crucial part of the pharmacophore (Fig. 1), as it is able to set up strong charge-assisted hydrogen bonds with proprionate groups of hematin. This complies well with single-crystal X-ray diffraction outcomes on the CQ dihydrogen phosphate salt at 103 K[6], where H2PO4– ions form hydrogen-bonded pillars which strongly interact with positively charged chloroquine molecules. Comparison of the CQ crystal structure with those of various hydrated salts of PQ (NO3–, SO42–, H2PO4–), grown by advanced sol-gel methods, disclosed subtle analogies and differences in the non-covalent interaction networks of the two drugs, which are also related to their solubilities.
[1] L. Kořený, M. Oborník, J. Lukeš, PLoS Pathog. 2013, 9(1), e1003088.
[2] D.C. Warhurst J.C. Craig, K.S. Raheem, Biochem. Pharmacol. 2007, 73, 1910.
[3] M.S.Walczak, K. Lawniczak-Jablonska, A. Wolska, A. Sienkiewicz, L. Suarez, A.J. Kosar, D.S. Bohle J. Phys. Chem. B 2011, 115, 1145.
[4] J. Gildenhuys, T. Roex, T.J. Egan, K.A. De Villiers, J. Am. Chem. Soc. 2013, 135, 1037.
[5] G. Macetti, S. Rizzato, F. Beghi, L. Silvestrini, L. Lo Presti, Physica Scripta 2016, 91, 023001.
[6] G. Macetti, L. Loconte, S. Rizzato, C. Gatti, L. Lo Presti, Crystal Growth Des. 2016. 16, 6043
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Study of the key interactions in the self-recognition of the antimalarial drug chloroquine
Full text linkMalaria is a parasitic disease that causes thousands of deaths every year, especially in undeveloped countries. The Plasmodium protozoa, responsible of the infection, kill human red blood cells by digesting hemoglobin. Many compounds have been employed in the last century against malaria, but nowadays the increasing resistance of Plasmodium is becoming a very serious problem. New drugs are required and to this end it is desirable to quantitatively understand the role of different functional groups in determining effective pharmacophores.
This work focuses on chloroquine (CQ), a 4-aminoquinoline antiplasmodial whose effectiveness is now hampered by evolved parasite resistance. It is accepted that CQ interferes with a crucial detoxification process of the parasite [1], namely the inhibition of heme bio-crystallization, but several details of this process still remain rather obscure. In the acidic digestive vacuole of Plasmodium, CQ is supposed to interact in its diprotonated form directly with the monomeric heme in two possible ways: 1) π-π stacking interactions between quinoline ring and heme proto-porphyrin [2] or 2) a direct Fe-N quinoline coordinative bond, supported by strong charge-assisted hydrogen bonds (CAHBs) between the tertiary amine of CQ and the propionate groups of heme [3-4].
In this work, the self-recognition of chloroquine diphosphate dihydrate salt was studied both theoretically and experimentally. High-resolution single crystal X-ray data were collected at low temperature (103 K) and complemented by quantum simulations with CRYSTAL14 [5] at the B3LYP/6-31G(p,d) theory level. The salt crystalizes in a P21/c structure, with phosphate ions forming infinite chains parallel to the b axis. CQ molecules and phosphates are connected through strong N-H•••O CAHBs, while a π-π interaction is present between the quinoline rings (see figure).
The topological analysis of the primary charge density, performed according with the Quantum Theory of Atoms in Molecules [6], along with the ab-initio energy decomposition, show that the coulombic interactions between the charged hydrocarbon chain of CQ and the phosphate ions seem to provide the dominant features in the molecular self-recognition, while the π-π stacking between the quinoline moieties has just an ancillary role. These evidences suggest that, in agreement with our previous DFT/EXAFS results [3], the protonated tertiary amine of CQ is an essential component of the drug pharmacophore.
[1] A. F. G. Slater, W. J. Swiggard, B. R. Orton, W. D. Flitter, D. E. Goldberg. A. Cerami and G. B. Henderson, Proc. Natl. Acad. Sci. USA 1991, 88, 325
[2] M. S. Walckzak, K. Lawniczak-Jablonska, A. Wolska, A. Sienkiewicz, L. Suarez, A. J. Kosar and D. S. Bohle, J. Phys. Chem. B 2011, 115, 1145
[3] G. Macetti, S. Rizzato, F. Beghi, L. Silvestrini and L. Lo Presti, Physica Scripta 2016, 91, 023001
[4] A. C. De Dios, R. Tycko, L. M. B. Ursos and P. D. Roepe, J. Phys. Chem. A 2003, 107, 5821
[5] R. Dovesi, V. R. Saunders, C. Roetti, R. Orlando, C. M. Zicovich-Wilson, F. Pascale, B. Civalleri, K. Doll, N. M. Harrison, I. J. Bush, P. D’Arco, M. Llunell, M. Causà and Y. Noël, CRYSTAL14 2014 CRYSTAL14 User's Manual. University of Torino, Torino
[6] R. F. W. Bader, Atoms in molecules. A quantum theory 1990, Oxford University Press. Oxford, U.K
Detection and kinetics of the single-crystal to single-crystal complete transformation of a thiiranium ion into thietanium ion
No full textThe conversion of a di-tert-butyl-methylthiiranium ion into thietanium ion, that is reported in the literature as taking place spontaneously at 25 °C in a CD2Cl2 solution, has been discovered to occur quantitatively at room temperature (RT) also in the crystalline state. The ring enlargement reaction is accompanied, in the solid phase, by a modest deterioration of the quality of the sample under investigation, and all three specimens here studied by in situ crystallography maintained their single-crystal nature up to 100% conversion. The rearrangement reaction implies the breaking of a C–S bond and the formation of a new bond of the same type, together with the migration of a methyl group . The extent of the corresponding atomic displacements has been measured by comparing the initial and final crystal structures. Several intermediate stages of the process have been investigated and characterized by the site occupancy factor of the episulfonium ion. The RT temporal evolution of this factor and that of the unit-cell volume indicate multi-step kinetics, with processes of simple molecular reorientation or displacement before and after the main, central stage, where the conversion reaction takes place. The overall kinetics is well described by an Avrami-Erofeev equation, with exponent m = 1.75(3) and rate coefficient k = 10.4(3) × 10−8 s−1 at 25 °C. Ab initio calculations in the gas phase predict a three-step mechanism resulting in a slightly spontaneous reaction with an overall decrease of entrop
Looking for indirect correlations among charge density and NLO properties: the case of a simple pyridinium tetrazolate
No full textThe development of novel second-order nonlinear optical (NLO) organic materials in the solid state is an important and growing research field, as it is attractive for laser industry, electro-optic devices, data safety issues, and so on. In recent decades, some experimental electron charge density studies have been performed on solid organic NLO-phores, aimed at extracting from the ground-state charge density the information on the hyperpolarizability tensor [1]. However, other groups [2] claimed that the one-particle charge density does not contain sufficient information to determine the NLO properties. Even though it is impossible to obtain reliable quantitative approximations of the beta tensor elements directly from the charge density, it is also true that the former are influenced by the molecular structure and intermolecular interactions. In this work, we look for possible indirect correlations between topological properties of the charge density and non-linear optical properties in a suitable, simple test-case. We focus on N-methyl pyridinium tetrazolate (PYRTE) [3], a high optical gap chromophore exhibiting high thermal, chemical and photochemical stabilities, whose NLO are observable only in solution due to the centrosymmetric crystal structure. First, we investigate how the crystal field affects molecular dipole moment, and therefore optical properties, of the solid. As expected, the in-crystal molecular dipole moment undergoes a significant enhancement, determining an important change in the second-order tensorial parameters of PYRTE. We then compare the predicted hyperpolarizability of the title compound with that of suitable chemical derivatives. Possible correlations among non-local integral topological descriptors, such as the Source Function, and the computed second order hyperpolarizabilities are tentatively established. Eventually, we look for possible PYRTE derivatives that, while maintaining good predicted NLO properties, are also potentially able to crystallize in non-centrosymmetric space groups. To this end, the CLP model [4] is applied to rank in silico generated structures from a thermodynamic viewpoint.
Acknowledgments: F. Beghi gratefully acknowledges travel support by AIC (Italian Crystallographic Association).
[1] T. S. Koritsanszky et al. Chem.Rev. 2001, 101, 1583
[2] A. E. Whitten et al. J. Chem. Phys. 2006, 125, 174505
[3] Beverina et al. Chem. Comm. 2011, 47, 292
[4] Gavezzotti, The Coulomb-London-Pauli (CLP) model of intermolecular interaction: Description and User’s Manual v. 3.6.2013; Milano, 2013
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Understanding self-recognition in the antimalarial drug chloroquine: an experimental and theoretical charge density study
No full textMalaria is the topmost world parasitic disease, with hundred of thousand deaths for year, most of which drug. In this context, the present work focuses on the experimental and theoretical characterization of chemical bonds and intermolecular interactions in crystalline CQ [1]. Chloroquine diphosphate salt was crystallized by various methods, including sol-gel techniques. Single-crystal X-Ray data collections were performed among room temperature (RT) and 100 K, using a Mo Ka source. CQ is a di-cation with protonated basic functions on quinolone. In the solid-state, complex patterns of hydrogen bonds (HBs) involving both the phosphate groups and co-crystallized water molecules are set up. Phosphate ions form infinite chains parallel to the monoclinic b axis, while CQ molecules keep their fused ring system orthogonal to the chains (see the Figure), setting in the free space among them through allegedly strong N–H···O HBs. The role of the two water molecules is less clear, even though they should help to coordinate phosphate ions. Even at 100 K, the X-ray data were not able to unequivocally determine the exact position of the H atoms. We therefore complemented the X-ray model by solid-state DFT simulations, but at least one water hydrogen has no obvious close acceptors and some kind of disorder cannot be excluded. On the basis of the solid-state DFT model, we applied the Hansen-Coppens multipolar approach [2] to study the experimental charge density in CQ diphosphate. The effect of the crystal field on the molecular conformation and the self-recognition energetics were investigated by both topological and quantum mechanical approaches. The importance of different intermolecular interaction patterns in setting up a stable crystal field is discussed. Acknowledgments: G. Macetti gratefully acknowledges travel support by AIC (Italian Crystallographic Association). This work has been supported by Unimi Development Plan – Line B1 and CINECA – ISCRA C (QUADRUG).
[1] Karle et al. Acta Crystallogr . 1988, C44, 1605.
[2] Hansen et al. Acta Crystallogr. 1978, A34, 90
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