Ligand-receptor interactions

Transcription

1 University of Silesia, Katowice, Poland March 2013 Ligand-receptor interactions Dr. Pavel Polishchuk A.V. Bogatsky Physico-Chemical Institute of National Academy of Sciences of Ukraine Odessa, Ukraine

2 Interactions 2

3 Receptors and ligands Receptive substance Receptor, Pharmacophore Lock-and-key paradigm 3 Langley, 1878 Paul Ehrlich, 1900 Emil Fisher, 1894 Lock-and-key paradigm

4 Ligand-receptor interaction 4 [R] [L] [RL] at 37 C

5 Protein Data Bank (PDB) 5

6 General aspects of protein-ligand interactions Enthalpy and enthropy 6 ΔG = ΔH - TΔS

7 Entropy-enthalpy compensation 7 In short, the tighter and more directed an interaction, the less entropically favorable it is. Bonding opposes motion, and motion opposes bonding.

8 Entropy-enthalpy compensation: Example 1 β-adrenoreceptor ligands 8 partial agonists antagonists agonists

9 Entropy-enthalpy compensation: Example 2 adenosine A1 receptor ligands 9 agonists antagonists

10 Cooperativity Thrombin inhibitors 10 ΔΔG -5.1 kj/mol ΔΔG = -8.6 kj/mol ΔΔG = kj/mol ΔΔG = kj/mol ΔΔG = -9.4 kj/mol Cooperativity = 18.0 ( ) = 4.3 kj/mol Muley L. et al, J. Med. Chem., 2010, 53 (5), pp

11 Desolvation and hydrophobic effects 11 Factor Xa inhibitors K i = 1 nm PDB: 2J4I K i = 39 μm

12 Structural water 12 Entropy gain up to 2 kj/mol

13 Structural water Wissner A. et al, J. Med. Chem., 2000, 43 (17), pp Inhibitors of Epidermal Growth Factor Receptor (EGFR) Kinase 13 IC μm IC μm

14 Campiani G. et al, Bioorganic & Medicinal Chemistry Letters, 1998, 8 (11), Structural water Inhibitors of acetylcholinesterase (AChE) 14 Huperzine Catechol Analogue

15 Structural water Overlay of 15 PDE10 inhibitors 15

16 Specific interactions. Hydrogen bonding. 16 Distance preference

17 Hydrogen bonding. Angle preference Donor hydrogen acceptor > C=O H 120 Exception: sulfonyl 3. Carboxyl groups syn orientation is preffered 4. Aromatic acceptors deviation from the plane < 30

18 Hydrogen bonding. Barrat E. et al, Journal of Molecular Biology, 2006, 362, 5, Major urinary protein 18 Tyr120 Ile45 Leu101 Phe90 Phe38 K d = 1011 μm Leu54 K d = 0.63 μm K d = 0.18 μm

19 Hydrogen bonding. 19 Basicity H-bond strength

20 Hydrogen bonding: Empirical findings from CSD analysis 1. Cyclic amides and ethers are stronger acceptors than acyclic ones Electron-donating substituents in aromatic rings increase acceptor strength 3. Aromatic ether are weaker acceptor than aliphatic. 4. Sulfones and sulfonamides are weak H-bond acceptors and they can be found more often in hydrophobic environment or form weak H-bonds with C-H. PDB: 2FRA

21 Cooperativity of H-bonds 21 antiparallel β-sheet parallel β-sheet

22 Weak H-bonds kcal/mol (in gas) 1.5 kcal/mol (in gas) 2C3L (orange): K i = 8.5 μm 2C3K (green): K i = μm

23 Weak H-bonds 23 acceptor donor rare frequent

24 Weak H-bonds Thrombin inhibitors 24 K i = 1.6 μm K i = 0.26 μm Böhm H. et al, ChemBioChem, 2004, 5 (5),

25 Weak H-bonds Distance preference 25 distance to oxygen atom of amide bond

26 Halogen bonding 26 Ph-F Ph-Cl, Ph-Br, Ph-I σ-hole Wilcken R. et al, J. Med. Chem., 2013, 56 (4), pp

27 Halogen bonding 27 PDB: 1T4E Halogen bond Weak H-bond

28 Orthogonal multipolar interactions 28 antiparallel β-sheet

29 Orthogonal multipolar interactions 29 PDB: 2FL6 PDB: 3CS9

30 Orthogonal multipolar interactions 30 PDB: 1AU9 Böhm H. et al, ChemBioChem, 2004, 5 (5),

31 Orthogonal multipolar interactions 31

32 Halogen and aromatic rings CSD statistics 32

33 Typical good environment for halogen 33 C H X H H C C

34 Hydrophobic interactions 34 Hydrophobic effect 30 cal/(mol Å 2 ) for CH kcal/mol (3.5-fold increase in affinity) 1. Desolvation and cooperative effects 2. Optimal filling of the hydrophobic pocket is ~55%. Residual flexibility is important!

35 Hydrophobic interactions Example of optimal filling of hydrophobic pocket 35 Human serine protease DPP-IV inhibitors PDB: 3KWJ

36 Aryl-aryl and aryl-alkyl interactions 36 E calc = -2.5 kcal/mol E exp = kcal/mol more often in proteins

37 Aryl-aryl and aryl-alkyl interactions Quadrupole moments Stacking kcal/mol -0.3 kcal/mol -1.0 kcal/mol

38 height above plane (Å) Aryl-aryl and aryl-alkyl interactions PDB statistics 38 centroid shift (Å)

39 Aryl-aryl and aryl-alkyl interactions p38 MAP kinase inhibitors 39 IC 50 = 220 nm PDB: 2W26 IC 50 = 1.1 nm Hynes J. et al, J. Med. Chem. 2008, 51,4 16.

40 Aryl-aryl and aryl-alkyl interactions 40 Factor Xa inhibitors IC 50 = 43 nm PDB: 2W26 IC 50 = 0.7 nm Roehrig S. et al, J. Med. Chem. 2005, 48,

41 Cation π interactions Lys 41 Arg kcal/mol (in buried pockets) Trp His PDB: 1LAF PDB: 1LST

42 Cation π interactions 42 Factor Xa inhibitors 9800 nm 911 nm 58 nm 9 nm PDB: 2BOC 550 nm

43 Improvement of binding affinity Improving ligand-protein interactions over those with the solvent in order to obtain a favorable (negative) change in enthalpy. 2. Making the ligand more hydrophobic in order to make the solvation entropy large and positive. 3. Pre-shaping the ligand to the geometry of the binding site in order to minimize the loss of conformational entropy upon binding.

44 Recommended literature 44 Caterina Bissantz, Bernd Kuhn, and Martin Stahl A Medicinal Chemist s Guide to Molecular Interactions Journal of Medicinal Chemistry, 2010, Vol. 53, Rainer Wilcken, Markus O. Zimmermann, Andreas Lange, Andreas C. Joerger and Frank M. Boeckler Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology Journal of Medicinal Chemistry, 2013, Vol. 56,