Pharmacokinetically based mapping device for chemical space navigation

ChemGPS, the chemical global positioning system, is a tool that combines rules (equivalent to dimensions) and objects (chemical structures) to provide a consistent chemical 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 molecules (objects) were used in conjunction with the VolSurf (http://www.moldiscovery.com) descriptors (rules), which are relevant for ADME (absorption, distribution, metabolism, 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) (http://www.fda.gov/cder/OPS/BCS_guidance.htm), in particular with respect to permeability and solubility. 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, respectively. The second GPSVS principal component correlates, without prior training, to solubility, as shown for the octanol-water partition and intrinsic solubility datasets, respectively. Although derived from principal component analysis, the two property axes rotate and form an angle of approximately 43degrees, thus being no longer orthogonal. GPSVS can be used to map the chemical space with respect to permeability and solubility, as recommended by FDA's biopharmaceutics classification system.