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A computational study on the impact of adding anionic groups to tyrosine kinase inhibitors
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Orientador(es)
Resumo(s)
This work focuses on improving the pharmacokinetics of tyrosine kinase inhibitors (TKIs) by modifying them from weak bases to weak acids, aiming to tackle multidrug resistance (MDR) in cancer treatment.
Tyrosine kinases play a crucial role in cancer therapy because of their involvement in cell growth and
differentiation pathways. The study explores the effects of these chemical modifications on the binding
affinities and pharmacokinetics of TKIs, especially in acidic tumor environments. We used molecular
docking and CpHMD simulations to systematically compare how well modified acidic TKIs perform
compared to traditional weak base TKIs.
The molecular docking results show that while modifying TKIs into weak acids has a minor effect on
their binding affinities, it can enhance their stability. The CpHMD simulations further showed that the
structural integrity of protein-ligand complexes is maintained even after modification, with stable RMSD
values and favorable binding modes across different complexes.
This study provided insights that could improve cancer treatment by addressing MDR and exploring
how altering the balance between protonation states and the resulting charges of TKIs might enhance drug
delivery and effectiveness.
Descrição
Tese de mestrado, Bioinformática e Biologia Computacional, 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
TKIs MDR Alteração Química Simulações Protonação Teses de mestrado - 2024