Biomedical Engineering Reference
In-Depth Information
doctrine can be observed in countries, where herbal medical preparations are still widely used.
Although the “Doctrine of Signatures” evidently is out of the conception of modern medicinal natu-
ral product research, the ideas of Paracelsus were the i rst approach to rational drug discovery.
More than 100 years ago, the mystery of why only certain molecules produced a specii c thera-
peutic response was rationalized by the ideas of Fischer and further elaborated by Langley and
Ehrlich that only certain cells contained receptor molecules that served as hosts for the drugs.
The resulting combination of drug and receptor created a new super molecule that had properties
producing a response of therapeutic value. One extension of this conception was that the drug i ts
the target specii cally and productively like “a key into its corresponding lock.” When the i t was
successful, a positive pharmacological action (agonistic) followed, analogous to opening the door.
On the contrary, a i t which prevented the intrinsic key to be inserted an antagonist action resulted—
i.e., the imaginative door could not be opened. Thus, if one had found adventitiously a ligand for a
receptor, one could rei ne its i t by opportunistic or systematic modii cations of the drug's chemical
structure until the desired function was obtained.
This productive idea hardly changed for the next half century and assisted in the development of
many useful drugs. However, a less fortunate corollary of this useful picture was that it led to some
limitations of creativity in drug design. The drug and its receptor (whose molecular nature was
unknown when the theory was formulated) were each believed to be rigid molecules precrafted to
i t one another precisely. Today, we know that receptors are highly l exible transmembranal glyco-
proteins accessible from the cell surface that often comprise more than one drug compatible region.
Further complexities have been uncovered continually. For example, a number of receptors have been
shown to consist of clusters of proteins either preassembled or assembled as a consequence of ligand
binding. The component macromolecules may be either homo- or heterocomplexes. The challenge of
developing specii c ligands for systems of this complexity may readily be imagined (Chapter 12).
The opposite extreme to lock and key is the zipper model. In this view, a docking interaction
takes place (much as the end of a zipper joins the talon piece) and, if satisfactory complementarity
is present, the two molecules progressively wrap around each other and adapt to the steric needs
of each other. A consequence of accepting this mutual adaptation is that knowledge of the receptor
ground state may not be particularly helpful as it adjusts its conformation to ligand binding. Thus,
in many cases one now tries to determine the three-dimensional structure of the receptor-ligand
complex. In those cases where x-ray analysis remains elusive, modeling of the interactions involved
is appropriate. This is the subject of Chapters 1 through 3.
Earlier, it was also noted that enzymes could be modulated for pharmacological benei t. Enzyme
proteins share many characteristics with the glycoprotein components of receptors, although
enzymes catalyze biochemical reactions. Receptor ligands interact with the receptor glycoproteins
or with the interfaces between the macromolecular subunits of di- or polycomponent receptor com-
plexes and modify the conformation and dynamics of these complexes. Thus, neither receptor ago-
nists nor antagonists directly interfere with chemical reactions and are dissociated from the receptor
recognition sites structurally unchanged.
The reaction mechanisms underlying the function of the vast majority of enzymes have been
elucidated in detail, and based on such mechanistic information it has been possible to design a vari-
ety of mechanism-based enzyme inhibitors, notably
k
cat
inactivators and transition-state analogues,
many of which are in therapeutic use (Chapter 11). Until very recently, it was only possible to inhibit
enzyme action rather than facilitate it. Actually, diseases frequently result from excessive enzymatic
action, making selective inhibition of these enzymes therapeutically useful.
Much later, a number of other classes of receptors have been disclosed, explored, and exploited as
therapeutically relevant pharmacological targets. This heterogeneous group of receptors comprises
nuclear receptors operated by steroid hormones and other lipophilic biochemical mediators, a broad
range of membrane-ion channels (Chapter 13), DNA or RNA (Chapter 23), and a number of other
biostructures of known or unknown functions. These aspects will be discussed in different chapters
of this topic.
