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Pharmacokinetically Based Mapping Device for Chemical Space Navigation

Domenii publicaţii > Chimie + Tipuri publicaţii > Articol în revistã ştiinţificã

Autori: Oprea, Tudor I.; Zamora, Ismael; Ungell, Anna-Lena

Editorial: Journal of Combinatorial Chemistry, 4, p.258-266, 2002.


ChemGPS, the chem. global positioning system, is a tool that combines rules (equiv. to dimensions) and objects (chem. structures) to provide a consistent chem. space map (Oprea, T. I.; Gottfries, J. J. Comb. Chem. 2001, 3, 157-166.). Rules included, initially, general properties such as size, lipophilicity, and hydrogen bond capacity, while objects include „satellites”, intentionally placed outside the druglike space, as well as „core” objects, mostly orally available drugs. ChemGPS mols. (objects) were used in conjunction with the VolSurf ( descriptors (rules), which are relevant for ADME (absorption, distribution, metab., and excretion) properties. The combination of ChemGPS and VolSurf, GPSVS, was investigated with respect to the biopharmaceutics classification system, which is recommended by the Food and Drug Administration (FDA) (, in particular with respect to permeability and soly. The first GPSVS principal component correlates, with no further training, to passive transcellular permeability, as illustrated for the Caco-2, ghost erythrocyte, and blood-brain barrier datasets, resp. The second GPSVS principal component correlates, without prior training, to soly., as shown for the octanol-water partition and intrinsic soly. datasets, resp. Although derived from principal component anal., the two property axes rotate and form an angle of approx. 43°, thus being no longer orthogonal. GPSVS can be used to map the chem. space with respect to permeability and soly., as recommended by FDA’s biopharmaceutics classification system.

Cuvinte cheie: Computer program, ChemGPS, Combinatorial library, Drug design, Molecular structure-property relationship, Permeability, Pharmacokinetics, Solubility, VolSurf