MOLECULAR MODELING AND FOOTPRINTING STUDIES OF DNA MINOR-GROOVE BINDERS - BISQUATERNARY AMMONIUM HETEROCYCLIC-COMPOUNDS

We report new quantitative footprinting data which reveal differences in binding constants of bisquaternary ammonium heterocyclic compounds (BQA) with AT-rich DNA sites depending on the ligand structure and on the size and sequence of the DNA binding site. In an attempt to unders tand the dependence of binding affinity on the ligand structure we hav e performed quantum-chemical AM1 calculations on the BQA compounds and on subunits to explore the conformational space and to calculate the electronic and structural features of individual ligand conformations. Due to the properties of the rotatable backbone bonds, there is a lar ge number of possible conformations with almost equal energy. We prese nt a new method for the calculation of the radius of curvature of mole cular structures. Assuming that strong binders should have a shape com plementary to the DNA minor groove, this measure is used to select the optimum conformations for DNA-drug binding. The approach yields the c orrect ligand conformation for SN6999, for which an X-ray DNA-drug str ucture is known. The curvature of the optimum conformations of all lig ands is compared with the experimental binding constants. A correlatio n is found between curvature and binding constant provided other struc tural factors do not vary. Therefore, we conclude that within structur ally similar BQA compounds the extent of curvature is the relevant qua ntity which modulates the binding affinity.