| Abstract
| - DB921 and DB911 are benzimidazole-biphenyl isomers with terminal charged amidines. DB911has a central meta-substituted phenyl that gives it a shape similar to those of known minor groove bindingcompounds. DB921 has a central para-substituted phenyl with a linear conformation that lacks theappropriate radius of curvature to match the groove shape. It is thus expected that DB911, but not DB921,should be an effective minor groove binder, but we find that DB921 not only binds in the groove but alsohas an unusually high binding constant in SPR experiments (2.9 × 108 M-1, vs 2.1 × 107 M-1 for DB911).ITC thermodynamic analysis with an AATT sequence shows that the stronger binding of DB921 is dueto a more favorable binding enthalpy relative to that of DB911. CD results support minor groove bindingfor both compounds but do not provide an explanation for the binding of DB921. X-ray crystallographicanalysis of DB921 bound to AATT shows that an induced fit structural change in DB921 reduces thetwist of the biphenyl to complement the groove, and places the functional groups in position to interactwith bases at the floor of the groove. The phenylamidine of DB921 forms indirect contacts with the basesthrough a bound water. The DB921−water pair forms a curved binding module that matches the shapeof the minor groove and provides a number of strong interactions that are not possible with DB911. Thisresult suggests that traditional views of compound curvature required for minor groove complex formationshould be reevaluated.
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