Design of stapled DNA-minor-groove-binding molecules with a mutable atom simulated annealing method

Wynn L. Walker, Mary L. Kopka, Richard E. Dickerson, David S. Goodsell

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

We report the design of optimal linker geometries for the synthesis of stapled DNA-minor-groove-binding molecules. Netropsin, distamycin, and lexitropsins bind side-by-side to mixed-sequence DNA and offer an opportunity for the design of sequence-reading molecules. Stapled molecules, with two molecules covalently linked side-by-side, provide entropie gains and restrain the position of one molecule relative to its neighbor. Using a free-atom simulated annealing technique combined with a discrete mutable atom definition, optimal lengths and atomic composition for covalent linkages are determined, and a novel hydrogen bond 'zipper' is proposed to phase two molecules accurately side-by-side.

Original languageEnglish (US)
Pages (from-to)539-546
Number of pages8
JournalJournal of Computer-Aided Molecular Design
Volume11
Issue number6
DOIs
StatePublished - 1997
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

Keywords

  • DNA-minor-groove-binding molecules
  • Rational drug design

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