Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity.
OBJECTIVE
Three new computational strategies have been evaluated for their ability to predict intestinal membrane permeability to a series of endothelin receptor antagonists.


METHODS
The three methods were evaluated using a set of ten nonpeptide endothelin receptor antagonists. The simplest method, "the rule of five", is based on 2D parameters such as the number of potential hydrogen bonds, molecular weight and calculated lipophilicity. A method based on molecular mechanics calculations is used to calculate 3D parameters such as polar and non-polar parts of the molecular surface area. The third method uses quantum mechanics to calculate molecular properties related to the valence region.


RESULTS
Descriptors derived by the latter two methods correlated well with permeability coefficients of the endothelin receptor antagonists. On the other hand, the rule of five failed to discriminate between drugs with high and low permeability.


CONCLUSIONS
Molecular surface descriptors and descriptors derived from quantum mechanics are potentially useful for the virtual screening of the permeability of the intestinal membrane to endothelin receptor antagonists.
Stenberg
P
P
Department of Pharmaceutics, Uppsala Biomedical Center, Uppsala University, Sweden.
Luthman
K
K
Ellens
H
H
Lee
C P
CP
Smith
P L
PL
Lago
A
A
Elliott
J D
JD
Artursson
P
P
D000818:Animals; D001682:Biological Availability; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003106:Colon / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007189:Indans / Q000737:chemistry / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D008968:Molecular Conformation; D008970:Molecular Weight; D010539:Permeability; D011817:Rabbits; D012995:Solubility; D013499:Surface Properties
D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D007189:Indans