Computational design strategy of pharmaceutical co-crystals: A case study of anti-cancer drugs / Nadia Hanim Sabri
Thymidylate synthase (TS) is a biomarker for fluoropyrimidine-based chemotherapy that provides the sole intracellular de novo source of thymidylate, an essential precursor to DNA synthesis. Antifolate drug and fluoropyrimidine-based drug have potential to disrupt TS activity by nucleotide and ant...
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| Format: | Thesis |
| Published: |
2018
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| Online Access: | http://studentsrepo.um.edu.my/9593/1/Nadia_Hanim_Sabri.pdf http://studentsrepo.um.edu.my/9593/6/nadia_hanim.pdf http://studentsrepo.um.edu.my/9593/ |
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| Summary: | Thymidylate synthase (TS) is a biomarker for fluoropyrimidine-based chemotherapy
that provides the sole intracellular de novo source of thymidylate, an essential precursor
to DNA synthesis. Antifolate drug and fluoropyrimidine-based drug have potential to
disrupt TS activity by nucleotide and antifolate binding sites. Raltitrexed (tomudex) is
one of the antifolate drugs that inhibit TS by decreasing dihydropyrimide
dehydrogenase (DHFR) activity. Fluoropyrimidine-based drug remains the most
effective first-line treatment for colorectal cancer (CRC) by inducing thymidylate
deficiency and imbalances in the nucleotide that led to DNA incorporation. However,
most of the marketed drugs including these antifolate and fluoropyrimidine-based drugs
have the lack of efficiency due to low solubility and dissolution rate. This research
highlights an area in the computational chemistry of dual-drug co-crystals to improve
drug delivery by modifying their physical properties. The combination treatment of
raltitrexed with other anti-cancer agents has been verified through several types of
research. Thus, the potential of co-crystals as the cancer inhibitors in the presence of
raltitrexed have been carried out in this study. This present work discovered the
combination of raltitrexed with modified 5-FU based co-crystal (compound 1) that gave
a significant benefit of effectiveness and manageable toxicity via computational
approach. The molecular dynamics simulation results suggested that the compound 1
enhancing binding strength of raltitrexed to inhibit TS with binding free energy (-45.68
kcal/mol) compared to raltitrexed alone (-16.57 kcal/mol). |
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