| Titre : | EXPLORATION OF NEW ANTI-TUBERCULOSIS DRUGS BY TARGETING DIHYDROFOLATE REDUCTASE | | Type de document : | thèse | | Auteurs : | JAOUID OUSSAMA, Auteur | | Année de publication : | 2022 | | Langues : | Anglais (eng) | | Mots-clés : | World Health Organization (WHO) Tuberculosis Mycobacterium tuberculosis dihydrofolate reductase (Mt-DHFR) Structure-based virtual screening Molecular Docking Organisation mondiale de la santé (OMS) Tuberculose, Mycobacterium tuberculosis dihydrofolate réductase (Mt-DHFR) Criblage virtuel basé sur la structure Docking moléculaire | | Résumé : | Tuberculosis (TB) is one of the ten leading causes of death in the world and the main source of infection from a single infectious agent, the World Health Organization (WHO) states that one third of the world's population is now infected with TB, therefore the increase in TB treatment and so a series of drug-resistant strains have emerged, diagnosis and therapy of multidrug-resistant TB continues to be a major hurdle and is far from being fully solved. Given the urgency of the situation, the current study uses the advantages of virtual high-throughput screening approaches to identify molecules targeting Mycobacterium tuberculosis dihydrofolate reductase (Mt-DHFR), an enzyme critical for Mycobacterium tuberculosis proliferation. In the extension of the Mt-DHFR ligand pocket, there is a small hydrophobic pocket that hosts a glycerol molecule (GOL), this pocket does not exist in the human protein. Based on these data, our study explored new Mycobacterium tuberculosis specific inhibitors targeting Mt-DHFR by the in-silico approach. From a set of 8412 compounds, toxicity evaluation and validation of Lipinski and Veber's rule allowed to identify 11 new small molecules whose interaction with the target with and without glycerol were studied by Docking, the results were compared with 5 reference molecules chosen from the literature in addition to natural ligand of the target. Thus for the evaluation of specificity, these molecules were also tested on human DHRF, the results showed that Methotrexate is the best reference inhibitor and that the affinities of the molecules towards Mt-DHFR with glycerol are better than without glycerol, It is so 8 molecules present an affinity towards the bacterial enzyme with glycerol better than that of Methotrexate, also 9 presenting a better affinity than that of natural substrate, among which 3 have a weak affinity towards the human enzyme compared to the bacterial enzyme. In the light of the results obtained we propose 3 inhibitors of Mycobacterium tuberculosis targeting Mt-DHFR with better activity and interactions than the reference inhibitors and which conform to the rules of Lipinski and Veber supposed to have antitubercular potential. | | Numéro (Thèse ou Mémoire) : | MM0732020 | | Président : | Azeddine Ibrahimi | | Directeur : | Ilham Kandoussi | | Juge : | Mouna Ouadghiri |
EXPLORATION OF NEW ANTI-TUBERCULOSIS DRUGS BY TARGETING DIHYDROFOLATE REDUCTASE [thèse] / JAOUID OUSSAMA, Auteur . - 2022. Langues : Anglais ( eng) | Mots-clés : | World Health Organization (WHO) Tuberculosis Mycobacterium tuberculosis dihydrofolate reductase (Mt-DHFR) Structure-based virtual screening Molecular Docking Organisation mondiale de la santé (OMS) Tuberculose, Mycobacterium tuberculosis dihydrofolate réductase (Mt-DHFR) Criblage virtuel basé sur la structure Docking moléculaire | | Résumé : | Tuberculosis (TB) is one of the ten leading causes of death in the world and the main source of infection from a single infectious agent, the World Health Organization (WHO) states that one third of the world's population is now infected with TB, therefore the increase in TB treatment and so a series of drug-resistant strains have emerged, diagnosis and therapy of multidrug-resistant TB continues to be a major hurdle and is far from being fully solved. Given the urgency of the situation, the current study uses the advantages of virtual high-throughput screening approaches to identify molecules targeting Mycobacterium tuberculosis dihydrofolate reductase (Mt-DHFR), an enzyme critical for Mycobacterium tuberculosis proliferation. In the extension of the Mt-DHFR ligand pocket, there is a small hydrophobic pocket that hosts a glycerol molecule (GOL), this pocket does not exist in the human protein. Based on these data, our study explored new Mycobacterium tuberculosis specific inhibitors targeting Mt-DHFR by the in-silico approach. From a set of 8412 compounds, toxicity evaluation and validation of Lipinski and Veber's rule allowed to identify 11 new small molecules whose interaction with the target with and without glycerol were studied by Docking, the results were compared with 5 reference molecules chosen from the literature in addition to natural ligand of the target. Thus for the evaluation of specificity, these molecules were also tested on human DHRF, the results showed that Methotrexate is the best reference inhibitor and that the affinities of the molecules towards Mt-DHFR with glycerol are better than without glycerol, It is so 8 molecules present an affinity towards the bacterial enzyme with glycerol better than that of Methotrexate, also 9 presenting a better affinity than that of natural substrate, among which 3 have a weak affinity towards the human enzyme compared to the bacterial enzyme. In the light of the results obtained we propose 3 inhibitors of Mycobacterium tuberculosis targeting Mt-DHFR with better activity and interactions than the reference inhibitors and which conform to the rules of Lipinski and Veber supposed to have antitubercular potential. | | Numéro (Thèse ou Mémoire) : | MM0732020 | | Président : | Azeddine Ibrahimi | | Directeur : | Ilham Kandoussi | | Juge : | Mouna Ouadghiri |
|
Accueil
Affiner la recherche Faire une suggestionEXPLORATION OF NEW ANTI-TUBERCULOSIS DRUGS BY TARGETING DIHYDROFOLATE REDUCTASE / JAOUID OUSSAMA
