Contribution to drug design through computational studies ofseveral series of bioactive heterocyclic molecules

Almi, Imane (2021) Contribution to drug design through computational studies ofseveral series of bioactive heterocyclic molecules. Doctoral thesis, Université de mohamed kheider biskra.

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Abstract

Detoxification enzymes play an important role in cleaning the body from the toxins. These ones represent a hindrance to some drugs to fulfill their tasks, especially active compounds like anti-cancer drugs. These latter are considered to have a high degree of toxicity in the body, which makes them targeted by the previous enzymes. We refer in this study to GSTp1-1, which is included in the detoxification enzymes class II targeted by NBD derivatives. It has dual defense feature, namely: inhibition GSTp1-1 and prevent the formation of each of the following complexes JNK1-GSTp1-1 and theTRAF2-GSTp1-1, that causes prolonged stopping of the cell cycle and facilitates apoptosis of damaged cells. This is what made us in this study shed light on the modeling similar compounds, and to achieve this goal, we applied a set of methods adopted in the modeling of active materials of high biological quality. Among them, the QSAR Two-dimensional (2D-QSAR) coupled with a virtual examination, by using a technique similarity search. In addition, we concretized a three - dimensional stereo (3D-QSAR) which contains effective biological properties (Pharmacophore). This application resulted to determine a quantity of compounds bearing the same previously identified characteristics. Therefore, we put limits, selectivity features extracted from specialized references, to reduce and identify biologically the best. We make sure of the validity and safety of extracted models mentioned above by using several ways, namely: LOO-CV, external test set validation, fisher randomization, and cost analysis. As a final result of this research, we identified 28 new derivatives of NBD From both studies, at different inhibitory concentrations, micromolar unit (µM); the value of the half-maximal inhibitory concentration of a compound is 6.531 µM

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