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1 Sequential Screening S. Stanley Young NISS HTS Workshop October 25, 2002.

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Presentation on theme: "1 Sequential Screening S. Stanley Young NISS HTS Workshop October 25, 2002."— Presentation transcript:

1 1 Sequential Screening S. Stanley Young NISS HTS Workshop October 25, 2002

2 2 What are the problems? HTS data sets are very large. Mixture of mechanisms. Bioassay data measured with error. Search space is very large.

3 3 Statistical Analysis Corporate Collection Commercial Compounds Virtual Compounds Statistical Model Selected Compounds Initial Compounds Active Compounds Filters Screen Compounds

4 4 Find Multiple Chemical Classes

5 5 Separate Mixture into Components 10,000 x 20,000 Inactives

6 6 MAO Inhibitors NN-CC C(3,1)-6-C(1,2)

7 7 Individual versus Group (Compound versus Feature) Individual observations Distributions of means of 10 observations Distributions of means of 25 observations

8 8 Small Shifts = Big Gains N= N=23,232 Initial Screening Set Selected Compounds

9 9 Enrichment Results Assay Training Pachinko Ratio # x # Fail* # x # x # Fail* # x # x # x * Assay not stable over time.

10 10 Descriptors 1.Capture relevant chemical information. 2.Fast to compute. 3.Easy to interpret. 4.Not too many.

11 11 Memorize versus Generalize Atoms / Functional Groups : -OH O(1,0) O(C ) HBD HBA =O O(1,1) O(C ) HBA Molecular twins in data sets.

12 12 Definition of Terms Example: Pharmacophores for estrogen receptor (ER) –1D: Molecular Volume: Å –2D: –3D: H-bond Donor H-bond Acceptor 7-10Å 2.5-4Å 10-14Å

13 13 DE ABC Conformer 1 X Y Z RW Y SV Example of a conformer fingerprint ……….. Fingerprint Number PharmPrint: Theory C AB X Y Z D AC X Y Z D AB X Y Z C AB W Y Z D AC W Y Z E DB W Y R C DB W Y R Conformer 1

14 14 Fragment Molecular Descriptors Atom pair N(3,0) S(2,0) Atom triple N(3,0) S(2,0) S(2,0) N(2,0) N(3,0) N(2,0) Topological torsion N(3,0)C(2,0)-1-C(3,1)O(2,0)

15 15 Fragment Molecular Descriptors Augmented Atoms N(CCC), S(CC) Augmented Atom Pair N(CCC) S(CC)

16 16 Carry out Partial Least Squares Analysis (PLS) Use both active compounds and inactive compounds PharmPrint : Theory Cx Molecule Molecule 2 … Molecule Molecule X Molecule X-1 :::: :::: … :::: 3-point FingerprintsActivitiesCoefficients C3 C2 C1 Cx :::: = X

17 17 Example Catalyst Pharmacophore Features Aliphatic Hydrophobe Hydrogen bond acceptor Aromatic Hydrophobe Hetero-atom Projected location of hydrogen Aromatic Ring Hydrogen bond donor

18 18 Model of AR Binding Site (Cool Picture) ARG752 GLN711 ASN Å 3.04 Å 2.79 Å 3.24 Å Å


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