Drug-receptor Interactions PDF

Drug-receptor interactions Module TWO 1  2 “Corpora non agunt nisi fixate” (a drug will not work unless it is bound) How can we maximise binding? 1854-1...

Drug-receptor interactions Module TWO 1  2 “Corpora non agunt nisi fixate” (a drug will not work unless it is bound) How can we maximise binding? 1854-1915  3 Drug-receptor interactions § Molecular recognition summarises all noncovalent and energetically favourable interactions between a small molecule and its receptor § Such binding events can change the nature or function of a protein, transform the shapes and dynamic behaviour of proteins, which translates in the modulation of the biological properties of proteins § The two fundamental aspects that govern molecular recognition events are shape and electronic complementarity between the interacting partners § Due to aqueous systems, desolvation and resolvation events need to be taken into consideration  4 Gibbs free energy of binding § Kd is a directly expressed free energy of interaction and can be defined by changes in enthalpy and entropy § -RT ln(Ka) = RT ln(Kd) = ΔG = ΔH – TΔS 1 KJ/mol = ~0.24 kcal/mol  5 Useful GENERAL rules § Experimentally determined Kd values are between 10-2 and 10-12 M, corresponding to Gibbs free energies of binding ranging from -10 to -70 KJ/mol. § A change in free energy by 5.7 kJ/mol alters the Kd by one order of magnitude § For SMALL molecules (up to 15 non-H atoms) each additional atom increases affinity by 6.3 kJ/mol § For larger molecules the binding affinities level off due to enthalpy-entropy compensation  6 Main factors that govern molecular interactions § There are physical phenomena that contribute to molecular recognition through the formation of noncovalent interactions. These can be expressed in terms of induction, dispersion, and electrostatic energy, and define polar and nonpolar interactions § Polar interactions (e.g., hydrogen bonds, salt bridge-reinforced hydrogen bonds) contribute the majority of the enthalpic component of the Gibbs free energy of binding and have been suggested to be a leading factor in determining selectivity of ligands § Nondirectional dispersion interaction of lipophilic moieties buried in well-defined hydrophobic pockets often contribute significantly toward the total affinity of a ligand. Lipophilic interactions have a relatively long range in aqueous environment and the released energy is a consequence of a largely entropically driven process, the de- wetting of hydrophobic surfaces  7 Non-bonded interac@ons § Through space interactions largely comprise van der Waals interactions and electrostatic interactions Recall: Coulomb potential between point charges where is the permittivity of free space, are atomic charges, and is the distance between and Recall: vdW dependence where is the Van der Waals well depth and is the distance at which How can we break these down into simple terms?  8 Distance dependence of noncovalent interac@ons Recall, that at very small distances, repulsive forces become significant: Example: interaction of two Ar atoms Lennard-Jones potential  9 Distance dependence of noncovalent interactions Recall: 10 Å = 1 nm (nanometre)  10 Energy of noncovalent interactions Bond Distance Approx. bond Approx. Dependence energy distance Covalent No simple ~ 200 KJ/mol 1.5 Å dependence Ionic Prop. 1/r < 20 KJ/mol 2.8 Å Hydrogen No simple < 10 KJ/mol 3.0 Å bond dependence (often < 3 KJ/mol) van der Waals Prop. 1/r6 < 5 KJ/mol 3.5 Å Hydrophobic No simple < 10 KJ/mol 3.5 Å dependence 1 KJ/mol = ~0.24 kcal/mol  11 Environmental effects on ionisation 3 3 3 3 Less basic Less basic more basic Less acidic more acidic Less acidic  12 Shape complementarity  13 Hydrogen bonds § Model as an electrostaZc interacZon between two dipoles consisZng of the H-N bond and the O sp2 lone pair. In electrostaZc theory, the opZmal orientaZon of two such dipoles is head-to-tail. The energy of such an arrangement should decrease as the head and tail are brought together as long as atomic van der Waals radii are not violated § “Ideal” hydrogen bond in this model would have r ~3.0 Å, p=180°, β=0° and γ=±60°. They are highly direcZonal! 1 KJ/mol = ~0.24 kcal/mol  14 Hydrogen bond donor strength  15 Hydrogen bond acceptor strength Carbonyl oxygen Pyridyl nitrogen Carboxylate oxygen Ether oxygen Sulfonyl oxygen J. Med. Chem. 2009, 52, 4073–4086  16 Hydrogen bond acceptor strength J. Med. Chem. 2009, 52, 4073–4086  17 Common hydrogen bonds in ac@ve sites  18 Halogen bonding § Can provide advantages over H-bonds § Halogen atomic radius along the extended R–X bond axis is smaller than in the direction perpendicular to this axis § Hydrogen bond acceptor: F>Cl>Br>I Halogen Bonding § Halogen bond donor: I>Br>Cl>F (5-180 kJ/mol) Hydrogen § Strength can be tuned like H-bonds π-π Stacking Ion-Dipole Bonding (50-200kJ/mol) (0-50 kJ/mol) (4-120 kJ/mol) § Polar hydrophobicity Dipole-Dipole vdW Forces Ion-Ion § Membrane permeability Close Packing (5-50 kJ/mol) (100-350 kJ/mol) Hydrophobic Effects Cation-π (