Virtual screening applied in several series of bioactive heterocyclic molecules

Khelfa, Nedjla (2024) Virtual screening applied in several series of bioactive heterocyclic molecules. Doctoral thesis, Université Mohamed Khider (Biskra - Algérie).

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Abstract

Malaria is one of the most widespread and fearsome parasitic disease in the world. Plasmodium falciparum is the parasite that causes the most severe type of malaria, this species transmits in the human body and attack the important organ; which is the human liver cells, will then reenter the blood stream and begin infecting the red blood cells. The major enzymes in this parasite is Plasmodium falciparum dihydrofolatereductase (PfDHFR), it is responsible for the biosynthesis of essential amino acids and nucleotide bases. The emergence of resistance of this kind of parasite to antimalarial agents had led for several years, still represents a threat, which draws our attention for the adoption of new guidelines for the treatment of malaria cases of P. falciparum species. For this reason, in this thesis we focus light on the discovery and development of Sym-triazine derivatives, which have provided a class of antimalarial drugs highly effective against PfDHFR. In this context, it is necessary to focus on Virtual Screening computational approaches in the fields of target identification and lead discovery. The aim of our study was to apply this type of in silico methodology, with the aim of modelling and evaluating for screening bioactive molecules derived from Sym-triazine. Our work combined between ligand-based VS methods; we based on the QSARs methods Two-dimensional (2D-QSAR(MLR/ANN)) and a three-dimensional stereo (3DQSAR( PLS)) which contains effective biological properties. The both of methods coupled with a Virtual Screening examination, by using a technique similarity search. Subsequently, we confirm the powerful and robustness of developed QSAR models by using various statistical OECD principles for the validation; internal and external validation (for training and test set), Y-randomization, and exploit of applicability domain. And structure-based VS methods; we concretized on the molecular docking analysis to determine the best interactions of the most active compound or the reference ligand which form stable complexes with the PfDHFR enzyme. The final results of our study, these different in silico methods allowed us to identify 9 new derivatives of Sym-triazine from both studies, show excellent inhibitory concentration activities against resistant P. falciparum bearing the mutant enzymes, making them good candidates for further development as antimalarial drugs.

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