title: Molecular modeling approaches for the prediction of the nonspecific binding of drugs to hepatic microsomes.
abstract: Molecular modeling approaches for the prediction of the nonspecific binding of drugs to hepatic microsomes were examined using a published database of 56 compounds. Models generated were evaluated using an independent test set of 13 compounds. A pharmacophore approach identified structural features of drugs associated with nonspecific binding. A side-chain amino group and complementary hydrophobic domain were the principal features noted. The use of shape overlays, based on the pharmacophore, in conjunction with a chemical force field in the program ROCS, yielded discrimination between molecules classified as strong binders (experimental fraction unbound in microsomes<0.50) and those with a lower degree of binding (experimental fraction unbound in microsomes>0.50). In the initial data set of 56 molecules, 18 were classified as strong binders (on the basis of the above criteria), and all of those were recovered in the top 22 molecular hits from ROCS. Additionally, computationally generated values of log P were shown to provide a reasonable estimate of the fraction unbound in microsomes, providing the compounds were in their basic form at physiological pH.
authors.affiliation: Department of Clinical Pharmacology, Flinders University and Flinders Medical Centre, Adelaide, Australia. matthew.sykes@flinders.edu.au
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sykes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sorich
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000737:chemistry / Q000187:drug effects*; D008956:Models, Chemical; D008958:Models, Molecular; D008962:Models, Theoretical; D008968:Molecular Conformation; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D007211:Indoles; C081308:FK 1052