1. Development of methods for the analysis of ligand-protein interactions by Maris Lapinsh; Advisor Jarl Wikberg Division of Pharmacology, Uppsala University ©Maris Lapinsh 2002

2. - Lapinsh et al. (2001) Development of proteo-chemometrics: a novel technology for the analysis of drug-receptor interactions. Biochim. Biophys. Acta, 1525(1). - Lapinsh et al. (2002) Proteo-chemometrics modeling of the interaction of amine G-protein coupled receptors with a diverse set of ligands, Mol. Pharm., 61(6). - Lapinsh et al. (2002) Classification of G-protein coupled receptors by alignment-independent extraction of principal chemical properties of primary amino acid sequences, Protein Sci., 11(4). ©Maris Lapinsh 2002

3. multiple linear regression, partial least-squares projections to latent structures, neural networks etc. - which ligand properties that are important for the recognition of the target protein - how to increase ligands affinity for the target - is any of the ligands selective for the given target - which ligand AND protein properties determine selectivity - how to improve selectivity for the target ©Maris Lapinsh 2002

4. - which ligand properties that are important for the recognition of the target protein - how to increase ligands affinity for the target - is any of the ligands selective for the given target - which ligand AND protein properties determine selectivity - how to improve selectivity for the target ©Maris Lapinsh 2002

5. Interaction data Lapinsh et al., Mol.Pharm., 2002. 1 ©Maris Lapinsh 2002

6. Molecular Interaction Fields Description of organic compounds and amino acids Bitstrings 2 ©Maris Lapinsh 2002

7. Molecular Interaction Fields 5 Z-scales Bitstrings Description of organic compounds and amino acids 2 ©Maris Lapinsh 2002

8. 5 Z-scales Description of organic compounds and amino acids 2 ©Maris Lapinsh 2002

9. Description of the whole protein sequences alignment basedalignment independent - Lapinsh et al. Classification of G- protein coupled receptors by alignment- independent extraction of principal chemical properties of primary amino acid sequences, Protein Sci., 2002. 3 ©Maris Lapinsh 2002

10. - Lapinsh et al. Classification of G- protein coupled receptors by alignment- independent extraction of principal chemical properties of primary amino acid sequences, Protein Sci., 2002. External prediction of membership to GPCR class 0% 97% ©Maris Lapinsh 2002

11. Ligand-protein cross description 4 ©Maris Lapinsh 2002

12. 21 amine G-protein coupled receptors 23 organic amines Application of proteo-chemometrics on amine GPCRs Lapinsh et al., Mol.Pharm., 2002. ©Maris Lapinsh 2002

13. Amine GPCRs Organic compounds 7 TM * 25 aa * 5 z-scales = 875 6 * 52 MIF descriptors = 312 Lapinsh et al., Mol.Pharm., 2002. -PCA? -”One way” analysis for variable selection? -Prior knowledge? -PCA on descriptor blocks? Ligand-receptor cross description ? ©Maris Lapinsh 2002

14. - Centering and scaling - Variable selection - Cross validation - Validation by responce permutations - External predictions Partial least-squares projections to latent structures ©Maris Lapinsh 2002

15. Lapinsh et al, Mol.Pharm., 2002. Output of PLS modelling: ©Maris Lapinsh 2002

16. Lapinsh et al, Mol.Pharm., 2002. Output of PLS modelling: ©Maris Lapinsh 2002

17. Lapinsh et al, Mol.Pharm., 2002. Average affinitySelectivity Properties important for ligands Output of PLS modelling: ©Maris Lapinsh 2002

18. Lapinsh et al, Biochim. Biophys. Acta, 2001. Output of PLS modelling: ©Maris Lapinsh 2002

19. Lapinsh et al, Biochim. Biophys. Acta, 2001. Output of PLS modelling: ©Maris Lapinsh 2002

20. Receptor sequence positions that affect interactions of each ligand Lapinsh et al, Mol.Pharm., 2002. Output of PLS modelling: ©Maris Lapinsh 2002

21. http://farm.farmbio.uu.se/maris/publ.html Papers available at: Maris Lapinsh supervisor Jarl Wikberg ©Maris Lapinsh 2002