Computational design principles for the discovery of bioactive dendrimers: [s]-triazines and other examples

Abstract

Introduction: Chemistry yields dendrimers of many classes and compositions. Translating this synthetic success to bioactivity is significantly aided by the use of computational modeling and our knowledge of the three-dimensional shapes of these macromolecules.

Areas covered: This review discusses the lessons learned during the investigations of [s]-triazine dendrimers. Specifically, the article focuses on the evolving role that computational models have taken in the exploration of these macromolecules. These lessons, furthermore, can be generalized across many dendrimer classes.

Expert opinion: Computational models and the resulting structural data from molecular dynamics simulations provide insights into: shape, solvent penetration, shielding of biolabile linkers, and the density of hydrophobic patches. These models have evolved from artistic representations, through bases for rationalization, to hypothesis-generating tools that drive synthesis. With further advances expected in both software and hardware the answer to the question, ‘What does a specific dendrimer look like in solution?' is becoming increasingly clear. Moreover, the authors believe that answer to this question lies at the heart of the design of bioactive dendrimers.

Keywords::

• bioactive materials
• computation
• covalent ligand attachment
• dendrimer
• design of dendrimers
• host-guest chemistry
• model
• molecular modeling
• non-covalent sequestration of guests
• radial distribution function
• shape
• triazine or [s]-triazine

Acknowledgments

Gas phase models of these triazine dendrimers were calculated by Kovacs and Perez of the Laboratory for Molecular Simulation at Texas A&M University. Models of the Toll-receptor antagonists were created by M Zloh of Imperial College London in a collaborative project led by S Shaunak. Bioactive studies including the use of triazine dendrimers as chemotherapeutics rely on the experimental efforts of collaborators from the University of Texas Southwestern Medical Center in Dallas including J-T Hsieh and X Sun.

Notes

This box summarizes key points contained in the article.