An index of electrotopological state for atoms in molecules

Kier, Lemont B.; Hall, Lowell H.; Frazer, Jack W.

doi:10.1007/bf01200825

Cited by 181 publications

(163 citation statements)

References 14 publications

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“…We used the topological descriptors provided by MOLCONN-Z software, version 3.50 (L. H. Hall, Eastern Nazarene College, Quincy, Mass. ), especially the Kier and Hall connectivity indices (up to the 10th order) and the electrotopological indexes (17,18). We also calculated some descriptors as charge indices (11) using Etopo 11, a computer software developed in our research unit.…”

mentioning

confidence: 99%

Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

Gozalbes

Brun-Pascaud

García-Domènech

et al. 2000

Antimicrob Agents Chemother

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We conducted a quantitative structure-activity relationship study using a database of 158 quinolones previously tested against Mycobacterium avium-M. intracellulare complex in order to develop a model capable of predicting the activity of new quinolones against the M. avium-M. intracellulare complex in vitro. Topological indices were used as structural descriptors and were related to anti-M. avium-M. intracellulare complex activity by using the linear discriminant analysis ( Mycobacteria belonging to the Mycobacterium avium-M. intracellulare complex are responsible for opportunistic infections in immunocompromised patients, especially those with HIV infection (29), and there is a need for new drugs that can be used for treatment and prophylaxis. Quinolones are good candidates because of their broad antibacterial spectrum, which includes atypical mycobacteria (16,22,25,30), together with their good tissue distribution and intracellular concentration (2). Ciprofloxacin and sparfloxacin are the only quinolones currently used against M. avium-M. intracellulare complex infection, but the incidence of strains resistant to these compounds is increasing, and there is a need for new derivatives.In addition to in vitro and in vivo tests, which are timeconsuming for the M. avium-M. intracellulare complex, powerful methodologies for drug design and drug database screening and selection are now available (7,19). Equation systems linking structure and activity (QSAR studies) are particularly relevant, and application of the mathematical models thereby obtained to large libraries of computer-generated compounds is known as virtual computational screening (5, 24). An important feature in this method is the use of good structural descriptors that are representative of the molecular features responsible for the relevant biological activity; a very useful technique for describing molecular structure is molecular topology, a two-dimensional QSAR method which takes into account the internal atomic arrangement of compounds. The structure of each molecule is represented by specific subsets of topological indices (TIs). Klopman et al. first developed computer-based predictive models to characterize anti-M. avium-M. intracellulare complex activity (20,21,23). The aim of this study was to develop new QSAR models, based on TIs, statistical linear discriminant analysis (LDA), and multilinear regression (MLR) in order to predict the in vitro activity and MICs of quinolones against the M. avium-M. intracellulare complex. MATERIALS AND METHODSThe study involved a number of steps, which are described in the following paragraphs.Obtaining structural descriptors by molecular topology. A database of 158 quinolones with known anti-M. avium-M. intracellulare complex activities has been built up from several articles by Klopman et al. (20,21,23). Each quinolone was characterized by a set of 145 TIs specific to each molecule. We used the topological descriptors provided by MOLCONN-Z software, version 3.50 (L. H. Hall, Eastern Nazarene College, Quincy...

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confidence: 99%

Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

Gozalbes

Brun-Pascaud

García-Domènech

et al. 2000

Antimicrob Agents Chemother

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“…Usual structural descriptions based on topological descriptors are based mainly on the whole molecule, and the QSAR models thereby obtained therefore offer little insight into drug pharmacophores. We therefore used of a new kind of topological descriptor-E-state indices-specific for each atom (12). Briefly, the E-state index of a given atom reflects its electronic and topological features, taking into account the interaction with the rest of the molecule, particularly the relationship between valence and sigma electrons.…”

Section: Methodsmentioning

confidence: 99%

Anti- Toxoplasma Activities of 24 Quinolones and Fluoroquinolones In Vitro: Prediction of Activity by Molecular Topology and Virtual Computational Techniques

Gozalbes

Brun-Pascaud

García-Domènech

et al. 2000

Antimicrob Agents Chemother

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The apicoplast, a plastid-like organelle of Toxoplasma gondii, is thought to be a unique drug target for quinolones. In this study, we assessed the in vitro activity of quinolones against T. gondii and developed new quantitative structure-activity relationship models able to predict this activity. The anti-Toxoplasma activities of 24 quinolones were examined by means of linear discriminant analysis (LDA) using topological indices as structural descriptors. In parallel, in vitro 50% inhibitory concentrations (IC 50 s) were determined in tissue culture. A multilinear regression (MLR) analysis was then performed to establish a model capable of classifying quinolones by in vitro activity. LDA and MLR analysis were applied to virtual structures to identify the influence of each atom or substituent of the quinolone ring on anti-Toxoplasma activity. LDA predicted that 20 of the 24 quinolones would be active against T. gondii. This was confirmed in vitro for most of the quinolones. Trovafloxacin, grepafloxacin, gatifloxacin, and moxifloxacin were the quinolones most potent against T. gondii, with IC 50 s of 0.4, 2.4, 4.1, and 5.1 mg/liter, respectively. Using MLR analysis, a good correlation was found between measured and predicted IC 50 s (r 2 ‫؍‬ 0.87, cross-validation r 2 ‫؍‬ 0.74). MLR analysis showed that the carboxylic group at position C-3 of the quinolone ring was not essential for anti-Toxoplasma activity. In contrast, activity was totally dependent on the presence of a fluorine at position C-6 and was enhanced by the presence of a methyl group at C-5 or an azabicyclohexane at C-7. A nucleophilic substituent at C-8 was essential for the activity of gatifloxacin and moxifloxacin.The discovery of a novel organelle in apicomplexan parasites and its characterization in Toxoplasma gondii offers new opportunities for pharmacological research on several protozoa of major medical importance (16). This organelle, the apicoplast, is a plastid-like structure which was probably acquired by secondary endosymbiosis from a green alga (15). The function of the apicoplast is still not clear, but the presence of this procaryotic structure within T. gondii presents a unique therapeutic target. Fichera and Roos showed that several antibiotics, such as azithromycin and ciprofloxacin, could inhibit DNA replication within the apicoplast and thus inhibited Toxoplasma growth (6). That study confirmed the previously wellknown effect of macrolides on T. gondii but also revealed fluoroquinolones as candidate anti-Toxoplasma drugs. However, other studies performed in vitro and in vivo failed to confirm the activity of ciprofloxacin against T. gondii and showed that, among the fluoroquinolones, only trovafloxacin and some of its derivatives inhibited Toxoplasma growth at micromolar concentrations (9, 10). Better knowledge of the structure-activity relationships of quinolones against T. gondii is thus needed.The aims of this work were (i) to assess quinolone activity against T. gondii by using a previously described model of virtual predicti...

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“…Third generation of topological indices is the hyper-Wiener index [6,7] or the molecular identiication (ID) numbers [8], the information indices [9][10][11], and the electrotopological state (E-state) indices [12,13].…”

Section: Quantitative Structure Activity Relationshipmentioning

confidence: 99%

Introductory Chapter: Some Quantitative Structure Activity Relationship Descriptor

Kandemirli¹

2017

Quantitative Structure-Activity Relationship

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An index of electrotopological state for atoms in molecules

Cited by 181 publications

References 14 publications

Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening

Anti- Toxoplasma Activities of 24 Quinolones and Fluoroquinolones In Vitro: Prediction of Activity by Molecular Topology and Virtual Computational Techniques

Introductory Chapter: Some Quantitative Structure Activity Relationship Descriptor

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