Computational design strategy of pharmaceutical co-crystals: A case study of anti-cancer drugs / Nadia Hanim Sabri

Nadia Hanim , Sabri (2018) Computational design strategy of pharmaceutical co-crystals: A case study of anti-cancer drugs / Nadia Hanim Sabri. Masters thesis, University of Malaya.

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Abstract

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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