Biomedical Engineering Reference
In-Depth Information
I.5.3.3 Membrane Penetration—Including Lipinski Rule of Five
In drug discovery projects, an issue of major importance is the design of drug molecules capable of pen-
etrating different biological membranes effectively and rapidly enough to allow effective concentrations
to build up at the therapeutic target. The structure and physiochemical properties of the drug molecule
obviously are of decisive importance, and it is possible to establish the following empirical rules:
Some small and rather water soluble substances pass in and out of cells through water lined
transmembrane pores.
Other polar agents are conducted into or out of cells by membrane associated and energy-
consuming proteins. Polar nutrients that the cell requires, such as glucose and many amino
acids, i t into this category. More recently, drug resistance by cells has been shown to be
mediated in many cases by analogous protein im- and exporters.
The blood-brain barrier (BBB) normally is not easily permeable by neutral amino acids.
However, such compounds with sufi ciently small difference between the p K a values will have
a relatively low I/U ratio indicating the ratio between ionized (zwitterionic) and unionized
molecules in solution. As an example, THIP (Figure I.4) has p K a values of 4.4 and 8.5 and a
calculated I/U ratio of about 1000. Thus, 0.1% of THIP in solution is unionized, and this frac-
tion permits THIP to penetrate the BBB very easily. Other neutral amino acids typically have
I/U ratios around 500,000 and thus very low fractions of unionized molecules in solution, and
such compounds normally do not penetrate into the brain after systemic administration.
Molecules that are partially water soluble and partially lipid soluble can pass through cell
membranes by passive diffusion and are driven in the direction of the lowest concentration.
In cells lining the intestinal tract, it is possible for molecules with these characteristics to
pass into the body through the cell membrane alone.
Finally, it is also possible for molecules with suitable water solubility, small size, and com-
pact shape to pass into the body between cells. This last route is generally not available for
passage into the CNS, because the cells are pressed closely together and thus closing off
these functions to form the BBB.
Whereas there are no guarantees and many exceptions, the majority of effective oral drugs obey the
Lipinski rule of i ve:
The substance should have a molecular weight of 500 or less
It should have fewer than i ve hydrogen-bond donating functionalities
It should have fewer than 10 hydrogen-bond accepting functionalities
The substance should have a calculated log
P (clog P ) between approximately −1 and +5
The Lipinski rule of i ve is thus not a rule comprising i ve paragraphs but simply an empirical rule,
where the number i ve occurs several times. The rule is a helpful guide rather than a law of nature.
I.5.3.4 Structure-Based Drug Design
During the early 1980s, the possibility to rationally design drugs on the basis of structures of thera-
peutically relevant biomolecules was an unrealized dream for many structural biologists. The i rst
projects were underway in the mid-1980s, and today, even though there are still many obstacles
and unsolved problems, structure-based drug design is an integral part of many academic and most
industrial drug discovery programs. In Chapter 2, a number of examples of this impressive drug
design approach are described.
As structural genomics, bioinformatics, and computational power continue to almost explode
with new advances, further successes in structure-based drug design are likely to follow. Each year,
new targets are being identii ed, structures of those targets are being determined at an amazing rate,
and our capability to capture a quantitative picture of the interaction between macromolecules and
ligands is accelerating.
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