title: Molecular modeling of arginine-glycine-aspartic acid (RGD) analogs: relevance to transepithelial transport.
abstract: OBJECTIVE
  The aim of this research is to model the effect of methylation on hydrogen bonding ability, surface area, polar surface area, volume, lipophilicity, charge, and cross-sectional diameters of a series of mono-, di-, and tri- methyl substituted analogs of arginine-glycine-aspartic acid (RGD) and compare these parameters to in vitro transport properties across Caco-2 monolayers.
  
  
  METHODS
  Molecular modeling was used to investigate the structural parameters that may influence the transport properties of RGD and its methyl analogs at pH 7.4. Log P was experimentally determined using a potentiometric method and compared to cLogP. Transport studies were carried out using Caco-2 cell monolayers.
  
  
  RESULTS
  Parameters such as polar and total surface area, volume, and Log P were found to vary with both the number and the sites of methyl substitution on the RGD molecule. The calculated as well as the experimental Log P values were found to be less than minus 2. The calculated maximum cross-sectional diameters ranged from 9 to 12 A. No detectable transport was noted.
  
  
  CONCLUSIONS
  Results of our study indicate that in the design considerations for the development of new peptidomimetic RGD analogs with enhanced oral bioavailability, an important parameter to consider is the three dimensional conformation of the peptides which influences their hydrogen bonding ability, polarity and molecular geometry.
authors: Department of Pharmaceutics, and Thad Cochran Center for the Development of Natural Products, University of Mississippi, University, Mississippi, USA.
authors: H
authors: H
authors: Ghandehari
authors: R
authors: R
authors: Sharan
authors: W
authors: W
authors: Rubas
authors: W M
authors: WM
authors: Killing
mesh_terms: D001692:Biological Transport; D018938:Caco-2 Cells; D017097:Electric Impedance; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid