BioPHYSICAL chemistry

58 PARTI THERMODYNAMICS AND KINETICS

differ in how they are regulated. Whereas

inhibitors for kinases have been identified

by random compound screening, few suc-

cessful drugs have been developed using

design principles. In recent design studies

(Noble et al. 2004; Ahn & Resing 2005;

Cohen et al. 2005), the ATP-binding site of

protein kinases has been targeted. At the site

is a gatekeeper residue that flanks a highly

variable hydrophobic portion of the ATP-

binding pocket. Differences in the size of this

residue as well as the surrounding amino acid

residues for different protein kinases have

been used to achieve selectivity. Protein

kinases can exist in inactive forms that are

also attractive for drugs.

Protein dynamics play a role in the affinity and kinetics of drug bind-

ing (Freire 2002; Teague 2003). The drug can be viewed as binding to

the lowest-energy state of the protein, which must undergo structural re-

arrangements in order to accommodate the drug. Due to protein dynamics,

multiple conformations of a protein are seen by a drug prior to binding

(Figure 3.7). In some cases, the drug binding can induce a substantial

conformational change due to the hydrophobic interactions between the

protein and drug. Although the overall energy of one conformation of

the protein may be at a minimum for the unbound complex, it may not

be the most favorable for drug binding, as the conformational changes

associated with drug binding can lead to a more stable complex for the

unbound conformation that has a larger energy.

Gibbs energy for an ideal gas

For an ideal gas, the change in the Gibbs energy can be directly related

to its thermodynamic parameters, such as the change in pressure. An

infinitesimal change in the Gibbs energy,dG, can be related to the enthalpy

and entropy according to dG=dH−TdS(eqn 3.19). Since the change in

enthalpy can be related to the total energy and the product of pressure

and volume (eqn 2.20), an infinitesimal change in the enthalpy,dH, is related

to the change in volume, dV, and the change in pressure, dP:

H=U+PV (3.24)

dH=dU+PdV+VdP

d(f(x)g(x)) =g(x)d(f(x)) +f(x)d(g(x))

PL

P*L

P*

ΔGobs

ΔGconvert

ΔGbarrier

P ΔGintrinsic

Protein energy profile Complex energy profile

Time

Energy

Figure 3.7
Dynamics result
in a protein having
several possible
conformations
(Pand P*) that
each has a different
overall energy. The
binding of a drug
can have different
interactions with
these conformations,
resulting in
significantly
altered energetics
for the drug–protein
complex yielding an
observed energy
change of ΔGobsfor
ligand binding.