title: Nonbonded bivalence approach to cell-permeable molecules that target DNA sequences.
abstract: Polyamides such as the natural antibiotic distamycin A can form binary or ternary complexes with B-DNA. The driving forces and advantages for forming the ternary complexes are not fully understood. The computational studies reported herein suggest that three- and four-ring polyamides have a propensity for forming the same dimer conformations in water as those in their ternary complexes. The pre-dimerization of a polyamide in water facilitates the formation of the ternary complex, making the polyamide more selective, and tighter binding to the minor groove whose minimal width is predetermined by the B-DNA sequence. Relative to the dimer tethered with covalent bonds, the smaller, monomeric polyamide available from reversible dimerization in water makes the molecule inherently more cell permeable. A nonbonded bivalence approach that dimerizes molecules by intermolecular interactions is proposed for improving affinity, selectivity, and cell permeability.
authors.affiliation: Computer-Aided Molecular Design Laboratory, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. pang@mayo.edu
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002463:Cell Membrane Permeability; D019295:Computational Biology; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D019281:Dimerization; D015195:Drug Design; D009757:Nylons / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D009757:Nylons; D014867:Water; D004247:DNA