21959096 11960484 2002 04 18 2002 05 10

0022-2623 45 9 2002 Apr 25 A computational ensemble pharmacophore model for identifying substrates of P-glycoprotein. 1737-40 P-glycoprotein (P-gp) functions as a drug efflux pump, mediating multidrug resistance and limiting the efficacy of many drugs. Clearly, identification of potential P-gp substrate liability early in the drug discovery process would be advantageous. We describe a multiple-pharmacophore model that can discriminate between substrates and nonsubstrates of P-gp with an accuracy of 63%. The application of this filter allows large virtual libraries to be screened efficiently for compounds less likely to be transported by P-gp. Penzotti Julie E JE Lamb Michelle L ML Evensen Erik E Grootenhuis Peter D J PD eng Letter

United States J Med Chem 9716531 0 P-Glycoprotein 150378-17-9 Indinavir 55985-32-5 Nicardipine IM Combinatorial Chemistry Techniques Databases, Factual Hydrogen Bonding Indinavir chemistry Models, Molecular Molecular Conformation Nicardipine chemistry P-Glycoprotein chemistry 2002 4 19 10 0 2002 5 11 10 1 ppublish 11960484 jm0255062 21959096 20353492 10893315 2000 08 03 2000 08 03 2000 12 18

0022-2623 43 14 2000 Jul 13 A rapid computational method for lead evolution: description and application to alpha(1)-adrenergic antagonists. 2770-4 The high failure rate of drugs in the development phase requires a strategy to reduce risks by generating lead candidates from different chemical classes. We describe a new three-dimensional computational approach for lead evolution, based on multiple pharmacophore hypotheses. Using full conformational models for both active and inactive compounds, a large number of pharmacophore hypotheses are analyzed to select the set or "ensemble" of hypotheses that, when combined, is most able to discriminate between active and inactive molecules. The ensemble hypothesis is then used to search virtual chemical libraries to identify compounds for synthesis. This method is very rapid, allowing very large virtual libraries on the order of a million compounds to be filtered efficiently. In applying this method to alpha(1)-adrenergic receptor ligands, we have demonstrated lead evolution from heterocyclic alpha(1)-adrenergic receptor ligands to highly dissimilar active N-substituted glycine compounds. Our results also show that the active N-substituted glycines are part of our smaller filtered library and thus could have been identified by synthesizing only a portion of the N-substituted glycine library. Molecular Design Group, CombiChem, Inc., 1804 Embarcadero Road, Suite 201, Palo Alto, California 94303, USA. Bradley E K EK Beroza P P Penzotti J E JE Grootenhuis P D PD Spellmeyer D C DC Miller J L JL eng Journal Article

UNITED STATES J Med Chem 9716531 0 Adrenergic alpha-Antagonists 0 Heterocyclic Compounds 0 Ligands 0 Receptors, Adrenergic, alpha-1 56-40-6 Glycine IM Adrenergic alpha-Antagonists chemistry Databases, Factual Drug Design Glycine analogs & derivatives chemistry Heterocyclic Compounds chemistry Ligands Models, Molecular Molecular Conformation Receptors, Adrenergic, alpha-1 chemistry 2000 7 14 11 0 2000 8 6 11 0 ppublish 0010893315 20353492 jm990578n