Biomedical Engineering Reference
In-Depth Information
with ritonavir, is known as Kaletra, and is an important salvage drug for patients who have failed
primary therapy with other protease inhibitors.
11.6 CONCLUDINGREMARKS
The structural details of drug-binding pocket interactions, gleaned from crystallographic and other
biophysical methods, can provide a rich source of information for inhibitor optimization. Historically,
SAR through structure-based methods has been limited by the time and protein demands of x-ray
crystallography. These limitations, however, are rapidly diminishing due to signii cant advances in
the technologies of protein expression and protein crystallography. In particular, robotic methods
for crystallization trials have signii cantly reduced the time required for obtaining crystals of a
target protein in complex with multiple inhibitory compounds. Likewise, the more routine use of
high-energy beam sources has facilitated structure determinations from crystals that would other-
wise not be sufi cient for diffraction studies. These advances provide the basis for greater reliance
on structural biology as a common tool during the iterative process of lead optimization.
Conformational dynamics within the drug-binding pockets of enzymes is a common feature,
dictated by the chemistry of enzyme catalysis. Hence, binding pocket structures are not static;
rather, they often change in response to encounters with inhibitory molecules. Thus, as described
in this chapter, there can often be a temporal component to enzyme-inhibitor afi nity. Advances in
kinetic methodologies and instrumentation have made the determination of inhibition kinetics more
facile, so that such measurements can be a routine part of the SAR of lead optimization. It is there-
fore no longer necessary to rely solely on equilibrium measures of inhibitor-binding afi nity, such
as IC 50 and K i values, for lead optimization. Instead, routine measurements of enzyme-inhibitor
association and dissociation rates are becoming practical, with throughput that makes these mea-
surements germane to drug discovery. Hence, increased attention is being paid to the importance of
understanding these kinetic components of drug-target interactions, and their potential impact on
clinical efi cacy. For example, the duration of drug efi cacy in vivo has been suggested to depend in
part on the duration of the drug-target complex; this is experimentally measured as the residence
time, which is the reciprocal of the dissociation rate constant for the drug-target complex. Drugs
that demonstrate long residence times, especially when this exceeds the pharmacokinetic half-life
of the drug, may signii cantly extend the pharmacodynamic efi cacy of a drug in vivo , and may also
ameliorate the potential for adverse events. Future drug discovery efforts may thus be focused not
merely on optimization of inhibitor afi nity, but also on the extension of residence time (see Further
Readings).
FURTHER READINGS
Copeland, R. A. (2000) Enzymes: A Practical Introduction to Structure, Mechanism and Data Analysis , 2nd
edn. Wiley, Hoboken, NJ.
Copeland, R. A. (2005) Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists
and Pharmacologists . Wiley, Hoboken, NJ.
Copeland, R. A., Pompliano, D. L., and Meek, T. D. (2006) Drug-target residence time and its implications for
lead optimization. Nat. Rev. Drug Discov ., 5 : 730-739.
Nagar, B., Bornmann, W. G., Pellicena, P., et al. (2002) Crystal structures of the kinase domain of c-Abl in com-
plex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res . 62 : 4236-4243.
Roberts, N. A., Martin, J. A., Kinchington, D., et al. (1990) Rational design of peptide-based HIV proteinase
inhibitors. Science 248 : 358-361.
Robertson, J. G. (2005) Mechanistic basis of enzyme-targeted drugs. Biochemistry 44 , 5561-5571.
Schramm, V. L. (2005) Enzymatic transition states: Thermodynamics, dynamics and analogue design. Arch.
Biochem. Biophys . 433 , 13-26.
Wood, E. R., Truesdale, A. T., McDonald, O. B., et al. (2004) A unique structure for epidermal growth factor
receptor bound to GW572016 (Lapatinib): Relationships among protein conformation, inhibitor off-rate,
and receptor activity in tumor cells. Cancer Res ., 64 : 6652-6659.
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