DESIGNER DNA-BINDING DRUGS - THE CRYSTAL-STRUCTURE OF A META-HYDROXY ANALOG OF HOECHST-33258 BOUND TO D(CGCGAATTCGCG)(2)

An analogue of the DNA binding compound Hoechst 33258, which has the p ara hydroxyl group altered to be at the meta position, together with t he replacement of one benzimidazole group by pyridylimidazole, has bee n cocrystallized with the dodecanucleotide sequence d(CGCGAATTCGCG)(2) . The X-ray structure has been determined at 2.2 Angstrom resolution a nd refined to an R factor of 20.1%, The ligand binds in the minor groo ve at the sequence 5'-AATTC with the bulky piperazine group extending over the C . G base pair, This binding is stabilised by hydrogen bondi ng and numerous close van der Waals contacts to the surface of the gro ove walls, The meta-hydroxyl group was found in two distinct orientati ons, neither of which participates in direct hydrogen bonds to the exo cyclic amino group of a guanine base. The conformation of the drug dif fers from that found previously in other X-ray structures of Hoechst 3 3258-DNA complexes. There is significant variation between the minor g roove widths in the complexes of Hoechst 33258 and the meta-hydroxyl d erivative as a result of these conformational differences. Reasons are discussed for the inability of this derivative to actively recognise guanine.