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Nicosia, Cyprus

Afantitis A.,Biomedical science Research Center Alexander Fleming | Afantitis A.,NovaMechanics Ltd | Melagraki G.,National Technical University of Athens | Sarimveis H.,National Technical University of Athens | And 3 more authors.
Molecular Diversity | Year: 2010

AnovelQSARworkflowis constructed that combines MLR with LS-SVM classification techniques for the identification of quinazolinone analogs as "active" or "nonactive" CXCR3 antagonists. The accuracy of the LS-SVM classification technique for the training set and testwas 100% and 90%, respectively. For the "active" analogs a validated MLR QSAR model estimates accurately their I-IP10 IC50 inhibition values. The accuracy of the QSAR model (R2 =0.80) is illustrated using various evaluation techniques, such as leave-one-out procedure (R2 LOO = 0.67) and validation through an external test set (R 2 pred = 0.78). The key conclusion of this study is that the selected molecular descriptors, Highest Occupied Molecular Orbital energy (HOMO), Principal Moment of Inertia along X and Y axes PMIX and PMIZ, Polar Surface Area (PSA), Presence of triple bond (PTrplBnd), and Kier shape descriptor (1κ), demonstrate discriminatory and pharmacophore abilities. Source

Afantitis A.,NovaMechanics Ltd | Melagraki G.,University of Cyprus | Koutentis P.A.,University of Cyprus | Sarimveis H.,National Technical University of Athens | Kollias G.,Biomedical science Research Center Alexander Fleming
European Journal of Medicinal Chemistry | Year: 2011

In this work we have developed an in silico model to predict the inhibition of β-amyloid aggregation by small organic molecules. In particular we have explored the inhibitory activity of a series of 62 N-phenylanthranilic acids using Kohonen maps and Counterpropagation Artificial Neural Networks. The effects of various structural modifications on biological activity are investigated and novel structures are designed using the developed in silico model. More specifically a search for optimized pharmacophore patterns by insertions, substitutions, and ring fusions of pharmacophoric substituents of the main building block scaffolds is described. The detection of the domain of applicability defines compounds whose estimations can be accepted with confidence. © 2010 Elsevier Masson SAS. All rights reserved. Source

Melagraki G.,University of Cyprus | Afantitis A.,NovaMechanics Ltd | Sarimveis H.,National Technical University of Athens | Igglessi-Markopoulou O.,National Technical University of Athens | And 2 more authors.
Chemical Biology and Drug Design | Year: 2010

In this study, quantitative structure-activity/property models are developed for modeling and predicting both MEK inhibitory activity and oral bioavailability of novel isothiazole-4-carboxamidines. The models developed are thoroughly discussed to identify the key components that influence the inhibitory activity and oral bioavailability of the selected compounds. These selected descriptors serve as a first guideline for the design of novel and potent MEK inhibitors with desired ADME properties. © 2010 John Wiley & Sons A/S. Source

Tzanetou E.,Agricultural University of Athens | Liekens S.,Rega Institute for Medical Research | Kasiotis K.M.,Benaki Phytopathological Institute | Melagraki G.,NovaMechanics Ltd | And 3 more authors.
European Journal of Medicinal Chemistry | Year: 2014

A series of novel isoxazole derivatives were efficiently synthesized through the adaptation/modification of an in situ synthetic procedure for pyrazoles. All novel compounds were tested against four different cell lines to evaluate their antiproliferative activity. Based on the Hela cells results of this study and previous work, a classification model to predict the anti-proliferative activity of isoxazole and pyrazole derivatives was developed. Random Forest modeling was used in view of the development of an accurate and reliable model that was subsequently validated. A virtual screening study was then proposed for the design of novel active derivatives. Compounds 9 and 11 demonstrated significant cytostatic activity; the fused isoxazole derivative 18 and the virtually proposed compound 2v, were proved at least 10 times more potent as compared to compound 9, with IC50 values near and below 1 μM. In conclusion, a new series of isoxazoles was exploited with some of them exhibiting promising cytostatic activities. Further studies on the substitution pattern of the isoxazole core can potentially provide compounds with cytostatic action at the nM scale. In this direction the in silico approach described herein can also be used to screen existing databases to identify derivatives with anticipated activity. © 2014 Elsevier B.V. All rights reserved. Source

Mouchlis V.D.,NovaMechanics Ltd | Melagraki G.,NovaMechanics Ltd | Mavromoustakos T.,National and Kapodistrian University of Athens | Kollias G.,Institute of Immunology | And 2 more authors.
Journal of Chemical Information and Modeling | Year: 2012

Molecular docking, classification techniques, and 3D-QSAR CoMSIA were combined in a multistep framework with the ultimate goal of identifying potent pyrimidine-urea inhibitors of TNF-α production. Using the crystal structure of p38α, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment for the generation of the CoMSIA fields. "Active" and "inactive" compounds were used to build a Random Tree classification model using the docking score and the CoMSIA fields as input parameters. Domain of applicability indicated the compounds for which activity estimations can be accepted with confidence. For the active compounds, a 3D-QSAR CoMSIA model was subsequently built to accurately estimate the IC 50 values. This novel multistep framework gives insight into the structural characteristics that affect the binding and the inhibitory activity of these analogues on p38α MAP kinase, and it can be extended to other classes of small-molecule inhibitors. In addition, the simplicity of the proposed approach provides expansion to its applicability such as in virtual screening procedures. © 2012 American Chemical Society. Source

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