Modification of anti-cancer co-crystal for thymidylate synthase inhibition: Molecular dynamics study

Sabri, Nadia Hanim and Halim, Siti Nadiah Abdul and Zain, Sharifuddin Md and Lee, Vannajan Sanghiran (2018) Modification of anti-cancer co-crystal for thymidylate synthase inhibition: Molecular dynamics study. Chiang Mai Journal of Science, 45 (6). pp. 2361-2373. ISSN 0125-2526,

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Raltitrexed (tomudex) is an alternative antifolate drug to 5-fluorouracil (5-FU) to inhibit thymidylate synthase (TS) by decreasing dihydrofolate reductase (DHFR) activity. The clinical trial shows the potential of raltitrexed towards TS inhibition can be enhanced by combining the raltiterexed with other anticancer agents. This present work discovered the combination of raltitrexed with modifying 5-FU based co-crystal (compound 1) have high effectiveness with manageable toxicity via computational approach. The X-ray structure of human TS (1HVY) was retrieved from Protein Database Bank. The molecular docking of protein-ligand complexes has been performed to investigate the potential of ligands as TS inhibitor by disrupting both promising binding sites; nucleotide and folate. The best-ranked conformations were further explored via parameterized molecular dynamic simulation. The simulated result by molecular dynamic simulation suggested that the modified co-crystal (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). Per-residue decomposition revealed that the Arg50A, Leu192A, Cys195A, His196A, Asn226 and Gly217A are the pivotal residues that playing main role in the nucleotide binding site. The binding free energy in the folate binding site is majority come from the interaction with Phe80A, Ile108A, Trp109A, Asp218A, Phe225A, Tyr258A, Met311A and Ala312A residues.

Item Type: Article
Uncontrolled Keywords: Colorectal cancer; raltitrexed; 5-fluorouracil (5-FU); compound 1; thymidylate synthase (TS); molecular dynamic simulation; MM-PBSA/GBSA
Subjects: Q Science > Q Science (General)
Q Science > QD Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 09 Apr 2019 03:28
Last Modified: 09 Apr 2019 03:28

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