The Docking Manoeuvre at a Drug Receptor: A Quantum Mechanical Study of Intercalative Attack of Ethidium and its Carboxylated Derivative on a DNA Fragment

Various semi-empirical quantum mechanical methods have been used to investigate the docking manoeuvre of ethidium and of its carboxylated derivative at the (dC-dG) • (dC-dG) receptor. The objective of the work was to determine whether the drug attacks the receptor in a random orientation or is pre-aligned for effective docking. An analogy was made between the interaction and two docking space vehicles. Charge distributions were computed for the intercalative site and the drug molecules; from these distributions it was possible to map, in three-dimensional space, the molecular electrostatic potential surrounding the receptor. Perturbation of the receptor fields by an approaching drug molecule showed field neutralization and a shifting local minimum as docking proceeds. Most of the electrostatic potential surrounding the receptor was shown to be derived from the two ionized phosphate groups. The orientation of the drug molecule was studied in a simplified anionic field constructed to reproduce that of the receptor phosphates. Rotation of ethidium and p-carboxyphenylethidium round the Eulerian axes in this simulated anionic field showed up distinct preferences for orientation of drug molecules in the vicinity of the receptor. Probability distributions for rotational populations demonstrated clearly that the receptor induces an orientation in the approaching ligand. The energy involved in modification of the alignment could be attributed to electrostatic interactions over large separation distances and to induced electron delocalization as the drug approaches closer to the receptor. This partition of the energy was considered further by monitoring electron migration in the drug molecules and analysis of dipole moment fluctuations. Orientation restrictions reflect entropy changes in the association reaction; these are discussed with respect to their importance in determination of reaction kinetics, and in two established models for drug- receptor interaction, namely, the ‘lock and key’ and ‘zipper’ mechanisms.