title: Non-covalent interactions involving halogenated derivatives of capecitabine and thymidylate synthase: a computational approach.
abstract: 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.
authors.affiliation: Bangladesh Institute of Computational Chemistry and Biochemistry, 38 Green Road West, Dhaka, 1205 Bangladesh ; Department of Chemistry, University of Dhaka, Dhaka, 1000 Bangladesh.
authors.forename: Adhip
authors.initials: A
authors.lastname: Rahman
authors.affiliation: Bangladesh Institute of Computational Chemistry and Biochemistry, 38 Green Road West, Dhaka, 1205 Bangladesh.
authors.forename: Mohammad Mazharol
authors.initials: MM
authors.lastname: Hoque
authors.affiliation: Department of General Studies, Jubail University College, Jubail Industrial City, 31961 The Kingdom of Saudi Arabia.
authors.forename: Mohammad A K
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, MB26, La Jolla, CA 92037 USA.
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Sarwar
authors.affiliation: Bangladesh Institute of Computational Chemistry and Biochemistry, 38 Green Road West, Dhaka, 1205 Bangladesh ; Institut Lumière Matière, Université Lyon 1 - CNRS, Université de Lyon, 69622 Villeurbanne Cedex, France.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Halim