Polar Interactions Involving Aromatic Ring Systems

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Other types of polar interactions often observed in ligand-protein complexes are n-n and cation-n interactions. The exact nature of these interactions is quite complex, but qualitatively they can be easily understood in terms of electrostatics. Figure 1.8 displays the calculated molecular electrostatic potential of benzene. It is obtained by calculating the energies of interaction between a benzene ring and a cation placed in different positions around the aromatic ring. The electrostatic potential in Figure 1.8 is color-coded on the vdW surface. A red color indicates a strong attraction between the cation and the aromatic ring and a blue color indicates a strong repulsion. Thus, a cation, for example an ammonium ion, may favorably interact with the face of the benzene ring, as shown in Figure 1.8. In n-n interactions, the edge of one benzene ring interacts with the face of the other.

Other aromatic rings such as phenol and indole display similar electrostatic potentials as benzene. Thus, the aromatic rings of phenylalanine, tyrosine, and tryptophan side chains may favorably interact with positively charged functional groups of the ligand. It has been estimated that a cation-n interaction may contribute by 8-17 kJ/mol to the overall binding of the ligand, which is equivalent to a 23- to 760-fold increase in affinity. Figure 1.9 shows the binding of nicotine to the

HH HH

FIGURE 1.8 The molecular electrostatic potential of benzene.

HH HH

FIGURE 1.8 The molecular electrostatic potential of benzene.

FIGURE 1.9 Nicotine in the binding pocket of the AChBP (pdb-code 1UW6).

AChBP. The binding displays a cation-n interaction between the ammonium group in nicotine and the indole ring system of Trp143.

dghydrophob—The Hydrophobic Effect

The hydrophobic effect is a concept used to describe the tendency of nonpolar compounds to transfer from water to an organic phase, for example, a lipophilic region of a protein. When a lipophilic compound is inserted into water it changes the dynamic network of hydrogen bonds between water molecules in pure liquid. It creates a new interface in which water molecules around the lipo-philic compound assume a more ordered arrangement than bulk water. This results in a decrease in entropy. Formation of a ligand-protein complex displaces the ordered water from the ligand and the protein into bulk water, as shown in Figure 1.10. The increased "freedom" of movement of the released water molecules gives an increase in entropy (AS) and, according to Equation 1.3, a more negative AG—an increase in affinity.

The magnitude of the hydrophobic effect is related to the area of hydrophobic surface that is buried in the binding cavity. Estimates, based on measurements of solvent transfer and ligand binding, range between 0.1 and 0.24 kJ/A2 mol. The burial of a methyl group of ca. 25 A-2 is thus expected to result in an affinity increase by a factor of 3-10. In cases of a more perfect fit between a methyl group and the protein, the affinity increase may be even larger.

Analysis of ligand-protein interactions and attempts at ligand design often focus on hydrogen bonding and other electrostatic interactions. However, in many cases even strong hydrogen bond interactions may favorably be replaced by hydrophobic interactions. An example of this is shown in Figure 1.11. The influenza neuraminidase inhibitor 1.1 binds to the protein with an affinity (IC50) of

FIGURE 1.10 The hydrophobic effect.

HO2C

NHAc

IC50=150 nM

NHAc

IC50= 1 nM

IC50=150 nM

IC50= 1 nM

FIGURE 1.11 Influenza neuraminidase inhibitors.

150 nM. According to the ligand-receptor x-ray structure, the binding displays a bidentate chargeassisted hydrogen bond between the terminal glycerol hydroxy groups and a glutamate side chain. Removal of the glycerol side chain as in analogue 1.2 and replacement with an hydrophobic alkyl group increases the affinity to 1 nM (the minor modifications of the six-membered ring are not expected to influence the affinity significantly). An x-ray structure of the protein complex (1.2) shows that the glutamate side chain is folded back, opening up a large hydrophobic pocket as indicated in Figure 1.11.

1.3.5 Agvdw—Attractive and Repulsive vdW Interactions

Nonpolar interactions between atoms, that is, vdW interactions, may be attractive as well as repulsive as shown by the vdW energy curve in Figure 1.12.

At short atom-atom distances, the vdW interaction is repulsive due to overlap of the electron clouds. The repulsion rises steeply with decreasing atom-atom distance in this region of the energy curve. When a part of the ligand clashes with atoms in the binding site, this steric repulsive vdW interaction is responsible for the often dramatic reduction in affinity that is observed.

At a longer distance, there is a region of attraction between the atoms. This attraction is due to the so-called dispersion forces. These are basically of electrostatic nature and due to interactions between temporary dipoles induced in two adjacent atoms. For a single atom-atom contact, the strength of the interaction is small, ca. 0.2 kJ/mol. However, as the total number of such interactions may be large, the dispersion interaction may in cases of a close fit between ligand and protein be significant. In this context it should be mentioned that the hydrocarbon tails in the core of a bilayer membrane are held together by dispersion forces.

As discussed in Section 1.3.5, a methyl group may be expected to increase the affinity of a compound by a factor of 3-10 due to the hydrophobic effect. Provided that the methyl group can be accommodated in the binding cavity. If it cannot be accommodated, vdW repulsion may instead give a significant decrease in affinity. Thus, the effect on the affinity of introducing a methyl group at different positions in a ligand may be a useful strategy to map out the dimensions of a receptor cavity in lack of experimental information on protein 3D-structure (see the discussion on pharmacophore modeling in Chapter 3). Provided that the introduced methyl group does not change the conformational properties of the parent molecule, the changes in affinity may be interpreted exclusively in terms of hydrophobic interactions and vdW interactions.

An example of effects that may be observed when introducing methyl groups in a ligand is shown in Figure 1.13. As discussed in detail in Chapter 3, flavone (1.3) binds to the benzodiazepine site of the GABAa receptor. The effects on the affinity of methyl groups in different positions of the parent flavone compound (1.3) may be interpreted in terms of properties of the binding cavity.

Energy

(J j Repulsion

(J j Repulsion

QQ Attraction o—o

QQ Attraction

FIGURE 1.12 The vdW energy curve.

Distance r

1.7 CH3

FIGURE 1.13 Affinities of methyl-substituted flavones binding to the benzodiazepine site of GABAa receptors.

1.7 CH3

FIGURE 1.13 Affinities of methyl-substituted flavones binding to the benzodiazepine site of GABAa receptors.

When a methyl group is introduced in the 6-position (1.4), the affinity is increased by a factor of 23. This indicates that the methyl group can be very well accommodated in a lipophilic cavity in the binding site and that the affinity increase is due to hydrophobic interactions including dispersion interactions. An introduction of a methyl group to the 4'-position in 1.4 to give 1.5 results in a 24-fold decrease of the affinity. This is most likely due to repulsive vdW interactions between the 4'-methyl group and the receptor giving an indication of the dimensions of the binding site in this region. An introduction of a 3'-methyl group in 1.4 to give 1.6 increases the affinity by a factor of 6. This is a significantly lower affinity increase than shown by the 6-methyl group in 1.4. Thus, the two receptor regions in the vicinities of the 6- and 3'-positions clearly have different properties. The region in the vicinity of the 3'-position can accommodate a methyl group but the fit between the methyl group and the receptor is not as good as in the case of the 6-methyl compound 1.4. This is supported by the modest change in affinity when larger substituents are introduced in the 3'-position (see Chapter 3). Finally, the introduction of a 5'-methyl group in 1.6 giving 1.7 strongly decreases the affinity by a factor of more than 52. This is undoubtedly due to strong repulsive vdW interactions with the receptor. This identifies another steric repulsive receptor region adjacent to that identified by compound 1.5. This example shows that conclusions drawn on the basis of a few compounds may provide valuable information on the properties of the protein binding site. Such information may be fruitfully used in the design of new compounds.

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