Entropy drug-receptor interactions

The entire drug discovery process, in particular at the cellular and animal level, has its own challenges [3] that contribute to the innovation deficif . It is thus imperative that computational tools deliver rapid and accurate models. At the molecular level, drug-receptor interactions continue to be too complex to provide failsafe in silico predictions [4] Entropy and the dielectric constant are but two examples of properties still under debate. The challenges of in silico drug discovery include the evaluation of multiple binding modes, accessible conformational... 

According to the equation (21.2), ligand-receptor interactions are characterized by enthalpy-entropy compensation in which one term favors and the other disfavors binding. While enthalpic contributions include electrostatic, hydrogen bond, and Van der Waals interactions, entropic contributions arise from several sources. On one hand, the loss of flexibility upon binding has an important entropic cost, counterbalanced on the other hand by the displacement of ordered water molecules. This will be discussed in the next section as well as the various types of drug-receptor interactions. 

As for van der Waals forces, hydrophobic interactions are individually weak (0.1 to 0.2 kJ moF for every square angstrom of solvent-accessible hydrocarbon surface ), but the total contribution of hydrophobic bonds to drug-receptor interactions is substantial. Similarly, the overall strength of the hydrophobic interaction between two molecules is very dependent on the quality of the steric match between the two molecules. If this is not sufficiently close to squeeze all of the solvent from the interface, a substantial entropy penalty must be paid for each of the trapped water molecules. 

Figure 3 Drug-receptor interactions. AHdw and AHrw are the enthalpies of hydration of the drug and the receptor, respectively, AHqr is the enthalpic contribution of the drug-receptor interaction, AS is the overall rotational and translational entropy in solution, and ASi , the internal rotational entropy of the free drug. ASw is the increase in entropy due to the release of hound water molecules (small circles) and ASvib the entropy gain due to low-frequency vibrational modes associated with the drug-receptor noncovalent interaction (reproduced from Figure 1 of ref [128] with permission from the American Chemical Society, Washington, DC, USA).

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