Protein structure--based drug design.
Design cycles will undoubtedly play an increasingly important role in drug discovery in the coming years, as the amount of structural information on protein targets continues to rise. However, the traditional method of drug discovery, based upon random screening and systematic modification of leads by medicinal chemistry techniques, will probably not be abandoned completely because it has a potentially important advantage over more structure-based methods--namely, leads identified in this way are unlikely to show a close resemblance to the natural ligand or substrate. They may, therefore, have advantages in terms of patent novelty, selectivity, or pharmacokinetic profile. However, such leads could then serve as the basis for structure-based, rational modification programs, in which their interactions with target receptors are defined (as we have described) and improved molecules are designed. A final important point to be made about structure-based design in drug discovery is that, while it can be of great use in the initial process of identifying ligands with improved affinity and selectivity in vitro, it can usually say very little about other essential aspects of the drug discovery process, e.g. the need to achieve an adequate pharmacokinetic profile and low toxicity in vivo. This observation reminds us that drug design is a multidisciplinary process, involving molecular biologists, biochemists, pharmacologists, organic chemists, crystallographers, and others. In order to be effective, therefore, structure-based design must be properly integrated into the overall discovery effort.
Whittle
P J
PJ
Pfizer Central Research, Sandwich, Kent, United Kingdom.
Blundell
T L
TL
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry; D001665:Binding Sites; D003139:Common Cold / Q000188:drug therapy; D003198:Computer Simulation; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors; D012229:Rhinovirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D013940:Thymidylate Synthase; D011683:Purine-Nucleoside Phosphorylase