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Chemography: The Art of Navigating in Chemical Space.

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

Autori: Oprea, Tudor I.; Gottfries, Johan.

Editorial: Journal of Combinatorial Chemistry, 3(2), p.157-166, 2001.


Combinatorial chem. needs focused mol. diversity applied to the drug-like chem. space (drugspace). A drugspace map can be obtained by systematically applying the same conventions when examg. the chem. space, in a manner similar to the Mercator convention in geog.: Rules are equiv. to dimensions (e.g., longitude and latitude), while structures are equiv. to objects (e.g., cities and countries). Selected rules include size, lipophilicity, polarizability, charge, flexibility, rigidity, and hydrogen bond capacity. For these, extreme values were set, e.g., max. mol. wt. 1500, calcd. neg. logarithm of the octanol/water partition between -10 and 20, and up to 30 nonterminal rotatable bonds. Only S, N, O, P, and halogens were considered as elements besides C and H. Selected objects include a set of „satellite” structures and a set of representative drugs („core” structures). Satellites, intentionally placed outside drugspace, have extreme values in one or several of the desired properties, while contg. druglike chem. fragments. ChemGPS (chem. global positioning system) is a tool that combines these predefined rules and objects to provide a global drugspace map. The ChemGPS drugspace map coordinates are t-scores extd. via principal component anal. (PCA) from 72 descriptors that evaluate the above-mentioned rules on a total set of 423 satellite and core structures. Global ChemGPS scores describe well the latent structures extd. with PCA for a set of 8599 monocarboxylates, a set of 45 heteroarom. compds., and for 87 a-amino acids. ChemGPS positions novel structures in drugspace via PCA-score prediction, providing a unique mapping device for the druglike chem. space. ChemGPS scores are comparable across a large no. of chems. and do not change as new structures are predicted, making this tool a well-suited ref. system for comparing multiple libraries and for keeping track of previously explored regions of the chem. space.

Cuvinte cheie: Computer program, ChemGPS, Combinatorial library, Drug design, Hydrogen bond, Lipophilicity, Molecular structure-property relationship, Polarizability