une approch computationnelle pour le développement d'agents thérapeutiques

Khelfaoui, Hdjer (2022) une approch computationnelle pour le développement d'agents thérapeutiques. Doctoral thesis, Université de mohamed kheider biskra.

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Abstract

Over the last few decades, computer-aided drug design (CADD) has established as a strong tool for developing novel therapeutic compounds. In computer-aided drug design, two methodologies are typically used: structure-based drug design and ligand-based drug design. Molecular docking combined with molecular dynamics is one of the most important tools of drug discovery and drug design, which it used to examine the type of binding between the ligand and its protein enzyme. Global reactivity has important properties, which enable chemists to understand the chemical reactivity and kinetic stability of compounds. The recent new contagion coronavirus 2019 (COVID-19) disease is a new generation of severe acute respiratory syndrome coronavirus-2 SARS CoV-2 which infected millions confirmed cases and hundreds of thousands death cases around the world so far. In this study, molecular docking and reactivity were applied for eighteen drugs, which are similar in structure to chloroquine and hydroxychloroquine, the potential inhibitors to angiotensinconverting enzyme (ACE2). Those drugs were selected from DrugBank. The reactivity, molecular docking and molecular dynamics were performed for two receptors ACE2 and Crystal structure SARS-CoV-2 spike receptor-binding with ACE2 complex receptor in two active sites to find a ligand, which may inhibit COVID-19. The results obtained from this study showed that Ramipril, Delapril and Lisinopril could bind with ACE2 receptor and Crystal structure SARS-CoV-2 spike receptor-binding with ACE2 complex better than chloroquine and hydroxychloroquine. The tyrosine kinase inhibitors gefitinib and erlotinib activated mutations of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer. Quinazolines and pyridopyrimidines are antibacterial, antifungal, and cancer-fighting compounds. The goal of this study is to look into the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a series of quinazolines and pyrido[3,4-d]pyrimidines as irreversible inhibitors of wild-type (WT) and L858R and T790M EGFR kinase domain mutants, as well as their reactivity, molecular docking, and molecular dynamics simulation. The 27 heterocycles under examination show a wide range of affinities for WT, L858R, and T790M, as well as strong chemical reactivity and kinetic stability. The compounds were found to have high ADMET characteristics, and pyrido[3,4-d]pyrimidines had good reactivity and affinity towards WT, L858R, and T790M mutations. New, powerful, irreversible tyrosine kinase inhibitors have been discovered.

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