Non-covalent interactions involving halogenated derivatives of capecitabine and thymidylate synthase: a computational approach
| Autor: | Mohammad A. K. Khan, Adhip Rahman, Mohammad Mazharol Hoque, Mohammed G. Sarwar, Mohammad A. Halim |
|---|---|
| Přispěvatelé: | University of Dhaka, Bangladesh Institute of Computational Chemistry and Biochemistry, Jubail University College, Scripps Research Institute, Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
In silico [CHIM.THER]Chemical Sciences/Medicinal Chemistry Thymidylate synthase Capecitabine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Molecule Non-covalent interactions chemistry.chemical_classification Multidisciplinary Trifluoromethyl biology Ligand Research Prodrug Combinatorial chemistry 3. Good health 030104 developmental biology chemistry Biochemistry 030220 oncology & carcinogenesis biology.protein [CHIM.CHEM]Chemical Sciences/Cheminformatics medicine.drug |
| Zdroj: | SpringerPlus SpringerPlus, SpringerOpen, 2016, 5, pp.146. ⟨10.1186/s40064-016-1844-y⟩ |
| ISSN: | 2193-1801 |
| DOI: | 10.1186/s40064-016-1844-y⟩ |
| Popis: | Capecitabine, a fluoropyrimidine prodrug, has been a frequently chosen ligand for the last one and half decades to inhibit thymidylate synthase (TYMS) for treatment of colorectal cancer. TYMS is a key enzyme for de novo synthesis of deoxythymidine monophosphate and subsequent synthesis of DNA. Recent years have also seen the trait of modifying ligands using halogens and trifluoromethyl (–CF3) group to ensure enhanced drug performance. In this study, in silico modification of capecitabine with Cl, Br, I atoms and –CF3 group has been performed. Density functional theory has been employed to optimize the drug molecules and elucidate their thermodynamic and electrical properties such as Gibbs free energy, enthalpy, electronic energy, dipole moment and frontier orbital features (HOMO–LUMO gap, hardness and softness). Flexible and rigid molecular docking have been implemented between drugs and the receptor TYMS. Both inter- and intra-molecular non-covalent interactions involving the amino acid residues of TYMS and the drug molecules are explored in details. The drugs were superimposed on the resolved crystal structure (at 1.9 Å) of ZD1694/dUMP/TYMS system to shed light on similarity of the binding of capecitabine, and its modifiers, to that of ZD1694. Together, these results may provide more insights prior to synthesizing halogen-directed derivatives of capecitabine for anticancer treatment. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-1844-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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