Quantitative structure–activity relationship studies of HIV-1 integrase inhibition. 1. GETAWAY descriptors

Saı́z-Urra, Liane; González, Maykel Pérez; Fall, Yagamare; Gómez, Generosa

doi:10.1016/j.ejmech.2006.08.005

Cited by 52 publications

(25 citation statements)

References 38 publications

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“…The 3D descriptors that better correlate with hepatotoxicity belong to the GETAWAY (GEometry, Topology, and Atom-Weight AssemblY) category. These descriptors are based on matching 3D-molecular geometry with chemical information, and are based on well-known accepted algorithms and formula, possessing a track record of good predictive power in biological property modeling [23,26]. The fact that hepatotoxicity correlates with 3D descriptors from a different category, when compared to the anti-HCC activity, is also an indication that the mechanism of action in both biological activities is probably different.…”

Section: Qsar Studies For Anti-hcc and Hepatotoxicity Activitiesmentioning

confidence: 99%

Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies

Abreu

Ferreira

Calhelha

et al. 2011

European Journal of Medicinal Chemistry

154

126

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a b s t r a c t Hepatocellular carcinoma (HCC) is a highly complex cancer, resistant to commonly used treatments and new therapeutic agents are urgently needed. A total of thirty-two thieno[3,2-b]pyridine derivatives of two series: methyl 3-amino-6-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates (1ae1t) and methyl 3-amino-6-[(hetero)arylethynyl]thieno[3,2-b]pyridine-2-carboxylates (2ae2n), previously prepared by some of us, were evaluated as new potential anti-HCC agents by studying their in vitro cell growth inhibition on human HepG2 cells and hepatotoxicity using a porcine liver primary cell culture (PLP1). The presence of amino groups linked to a benzene moiety emerges as the key element for the anti-HCC activity. The methyl 3-amino-6-[(3-aminophenyl)ethynyl]thieno[3,2-b]pyridine-2-carboxylate (2f) is the most potent compound presenting GI50 values on HepG2 cells of 1.2 mM compared to 2.9 mM of the positive control ellipticine, with no observed hepatotoxicity (PLP1 GI50 > 125 mM against 3.3 mM of ellipticine). Moreover this compound changes the cell cycle profile of the HepG2 cells, causing a decrease in the % of cells in the S phase and a cell cycle arrest in the G2/M phase. QSAR studies were also per-formed and the correlations obtained using molecular and 1D descriptors revealed the importance of the presence of amino groups and hydrogen bond donors for anti-HCC activity, and hydrogen bond acceptors for hepatotoxicity. The best correlations were obtained with 3D descriptors belonging to different subcategories for anti-HCC activity and hepatotoxicity, respectively. These results point to different molecular mechanisms of action of the compounds in anti-HCC activity and hepatotoxicity. This work presents some promising thieno[3,2-b]pyridine derivatives for potential use in the therapy of HCC. These compounds can also be used as scaffolds for further synthesis of more potent analogs.

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Section: Qsar Studies For Anti-hcc and Hepatotoxicity Activitiesmentioning

confidence: 99%

Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies

Abreu

Ferreira

Calhelha

et al. 2011

European Journal of Medicinal Chemistry

154

126

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“…Also, the presence of outliers can be detected by examining several statistics such as standard residual, Mahalanobis distance, deleted residual, and Cook s distance values. From these statistics, standard residual values are one of the most used in the literature [51,52] and has been established that values outside the range of AE 2 point to compounds considered outliers. For these reasons, in this study we plotted the leverage values calculated for every compound (X-axis) versus standard residuals (Y-axis).…”

Section: Identifying Outliersmentioning

confidence: 99%

Theoretical Prediction of Antiproliferative Activity against Murine Leukemia Tumor Cell Line (L1210). 3D‐Morse Descriptor and its Application in Computational Chemistry

et al. 2009

Self Cite

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Cancer is among the top ten causes of death in the world but in spite of the efforts of the pharmaceutical companies and many governmental organizations, new and more effective drugs are urgently needed. Computer-assisted studies have been widely used to predict anticancer activity taking into account different molecular descriptors, statistical techniques, cell lines, and datasets of congeneric and non-congeneric compounds. This paper describes a QSAR study and the successful application of 3D-MoRSE descriptor for developing Linear Discriminant Analysis (LDA) to predict the anticancer potential of a diverse set of indolocarbazoles derivatives. Despite the structural complexity of this sort of compounds the used variables are able to identify the most remarkable features like the incidence of polarizability of the substituents and the interatomic distance in the 7-azaindole moiety in the antiproliferative activity. A comparison with other approaches such as the Getaway, Randić molecular profile, Geometrical, RDF descriptors, was carried out showing the model with 3D-MoRSE descriptor resulting in the best accuracy and predictive capability. An LDA-based desirability analysis was conducted to select the levels of the predictor variables, in other words, the values of the independent variables which should generate more desirable anticancer chemicals, i.e., with higher posterior probability to be classified cytotoxic.

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“…The R-GETAWAY descriptors are defined based on the molecular influence ⁄ distance matrix R where the elements of the molecular influence matrix are combined with those of the geometry matrix. In fact, GETAWAYs have shown great potential as powerful variables in QSAR modeling of different biologic activities because they encode information about molecular shape, size and atom distribution (46,47). The H-GETAWAY descriptor HATS6m is a modification of the Moreau-Broto autocorrelation descriptor taking into account 3D-molecular geometry, using the atomic mass as atom weights.…”

Section: D-qsarmentioning

confidence: 99%

QSAR Studies on Aminothiazole Derivatives as Aurora A Kinase Inhibitors

Qin

et al. 2010

Chem Biol Drug Des

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Quantitative structure-activity relationship studies on 54 aminothiazole derivatives as Aurora A kinase inhibitors were performed to explore the important factors affecting their biologic activity. For 2D-quantitative structure-activity relationship study, genetic algorithm combined with multiple linear regression was used to select significant molecular descriptors. The MLR model gave squared correlation coefficient of 0.828 and squared cross-validated correlation coefficient of 0.771 for the training set compounds. Comparative molecular field analysis and comparative molecular similarity indices analysis were used to develop 3D-quantitative structure-activity relationship models. The comparative molecular field analysis model gave cross-validated correlation coefficient q 2 of 0.695 and non-cross-validated correlation coefficient r 2 of 0.977. For comparative molecular similarity indices analysis model, the corresponding q 2 and r 2 were 0.698 and 0.960, respectively. The proposed 3D-quantitative structure-activity relationship models were validated by the test set compounds not used in the modeling process, with r 2 pred values of 0.788 for comparative molecular field analysis and 0.798 for comparative molecular similarity indices analysis. The 3D contour maps suggested that further modification of the aniline group of compound 22 considering electrostatic, hydrophobic and hydrogen bond properties would influence the inhibitory activity. The results from quantitative structureactivity relationship models would be very useful to understand the structure-activity relationship of these inhibitors and to guide the further structural modification of new potential inhibitors.

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Quantitative structure–activity relationship studies of HIV-1 integrase inhibition. 1. GETAWAY descriptors

Cited by 52 publications

References 38 publications

Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies

Anti-hepatocellular carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies

Theoretical Prediction of Antiproliferative Activity against Murine Leukemia Tumor Cell Line (L1210). 3D‐Morse Descriptor and its Application in Computational Chemistry

QSAR Studies on Aminothiazole Derivatives as Aurora A Kinase Inhibitors

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