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

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Presentation transcript:

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

- 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

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

- 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

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

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

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

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

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., ©Maris Lapinsh 2002

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

Ligand-protein cross description 4 ©Maris Lapinsh 2002

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

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

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

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

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

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

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

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

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

Papers available at: Maris Lapinsh supervisor Jarl Wikberg ©Maris Lapinsh 2002