Why Aren't Drugs Safer? - Is It Because We Need A
Fundamental Understanding of the Receptor Response?
In order to create safer
pharmaceutical drugs, we need a fundamental understanding of the receptor
response. What does this mean? Basically we'd like to know how drugs activate
or deactivate their target receptors. This sounds simple enough, yet with all
of the research time and money that's been thrown at this problem we still
don't have agreement on the underlying biophysical mechanism for receptor activation
or response. Perhaps this partially explains why we miss some of the serious
side effects of drugs.
Scientifically
accurate descriptions of drug-receptor interactions should eventually lead to
better pharmaceuticals; therefore, this should be a top priority for future
pharmaceutical research. In this age of computers, one would think that
computer models would provide us with straightforward explanations for the
receptor response. Why hasn't this happened during the past few decades of
intense research?
Surprisingly, not
even the most modern computers are up to the task. This is due to problems that
include inadequate descriptions of the basic biophysical picture and the
inexact nature of our computer simulations. Also as many computer models become
increasingly complex, we lose the ability to "see" what is happening
at the level required for us to truly understand the underlying mechanism.
Although our computers provide us with large amounts of output, the complexity
of the computer code requires us to interpret the output in meaningful ways.
This is big business in pharmaceutical and academic research today.
However, in the face of
sometimes daunting scientific challenges, it is often prudent to limit one's
efforts to those parts of the picture that are amenable to our computational
simulations. This, however, may limit us to only incremental progress. As
scientists, we all like to believe that we're contributing meaningful work
toward solving particular problems. However, we know that we must be missing
key concepts that prevent a true breakthrough in our understanding of the
receptor response. On the other hand, there sometimes occurs a new concept
that's just so outrageous that it might be enough to provide the breakthrough
we need. This has certainly happened before in the history of science with the
caveat that a new concept usually isn't accepted quickly because most
scientists don't have enough time, energy, or motivation to check it.
With that warning, the
fundamental concept that prevents us from understanding receptor response is
how we define a relatively simple chemical concept called an equilibrium. This
may seem far removed from the study of biological receptors or even foolish
because the concept of chemical equilibrium seems so firmly established, but it
lies at the very core of the problem to model the receptors' behavior because
it is the perturbation of the equilibrium of the receptor that determines the
response.
The problem is that the true
chemical equilibrium is composed of multiple microstates interacting with many
other microstates of many other molecules in solution. A microstate is a
detailed configuration of a molecular system that includes specific molecular
conformations and interactions. The reality is that even with our most
sophisticated computers we can't account for all of the microstates comprising
a particular concentration within an equilibrium. To do this we would have to
calculate all of the different pH-dependent states interacting with the various
counterion binding states, which are an excessively large number of possible
combinations for modeling any proteins or receptors in solution. Therefore, in
our attempt to model molecular and chemical behavior, we lump these microstates
together into one state that we label a concentration.
Although these molecular
microstates are far too numerous to model, if one can discover a suitable
receptor model with a feasible biophysical mechanism for a two-state receptor system,
then one can test the predictions of such a model using various computational
simulations. These two-state systems also represent an obvious simplification
of the underlying microstates. However, over the years they have been useful in
describing drug-receptor systems in an on-off fashion and have recently made
something of a comeback in pharmacology theory.
For a simple two-state
receptor system with a binding molecule that reacts differently with either
side of a two-state equilibrium, there will be a stress created on the side of
the equilibrium that reacts the most with the binding molecule. This requires a
compensatory shift toward the more active side of the equilibrium to relieve
this stress. This shift has been known in chemistry for many decades as Le
Chatelier's principle. As strange as it may seem, we can make an analogy
between the poised chemical equilibrium of a receptor in either of two states
and a weighing on a simple beam balance. This allows us to see that the
chemical equilibrium is very similar to the behavior of a simple balance.
The reason has to do with the
underlying changes within the microstates comprising the chemical equilibrium
that increase the probability of a receptor molecule being on one side of the
equilibrium or the other (e.g. in
a simple two-state system). This is analogous to the addition of weights to
either side of a physical balance causing the balance to tip toward the more
weighted side. By altering the probabilities of the underlying receptor
microstates, the chemical equilibrium shifts and thereby represents something
more than the simple concentration expressions. Instead the shift represents a
change in the underlying probability distribution of microstates for the
chemical concentrations.
The mathematical calculation
for this shift requires that a ratio of states be constructed for two equal
processes. The calculation is the same for a simple balance where a
displacement may be obtained by either the addition of unequal weight to either
side or by the transfer of weight from one side of the balance to the other.
Combining the equivalent changes creates a fundamental equation for equilibrium
that allows us to solve for the initial shift.
One of the most fascinating
observations from this approach is that the solution for this initial shift
obeys a fundamental psychophysical law called Weber's law or the Weber-Fechner
law (see - Weber's Law Modeled by
the Mathematical Description of a Beam Balance, Mathematical Biosciences 122:
89-94 (1994)). Our sensory systems that depend on cellular receptors also
obey this law. Why would a simple
balance obey a law that also applies to our sensory perceptions? This
observation links the chemical equilibrium of receptors with the equilibrium of
a simple balance and further suggests a common mechanism between the physical,
chemical, biological and physiological realms. The mechanism is that the
perturbation of a two-state equilibrium that alters the underlying
probabilities makes one side of the equilibrium more or less likely than the
other side.
In pharmacology, this
perturbation or shift was never before calculated as a separate parameter and examined
to see whether or not it describes the drug-receptor response until a little
more than thirteen years ago when the theory was first conceived (see - A Method for determining drug
compositions to prevent desensitization of cellular receptors. U.S. Pat.
5,597,699 (1997) - note that this patent was originally begun in 1992).
Since then it has been tested a number of times both in vivo and in vitro and found to be a valid predictor of receptor response (see the most
recent results in - Optimal
Agonist/Antagonist Combinations Maintain Receptor Response by Preventing Rapid
Beta-1 adrenergic Receptor Desensitization Intl. J. Pharmacol., 1(2): 122-131,
2005 and http://www.bio-balance.com/Graphics.htm
for the derivation).
We now understand that
receptors function as poised chemical balances that can be shifted to either
side by unequal ligand binding. However, one of the more difficult concepts is
to explain how receptors
desensitize. This means that the receptor's response decreases in the
continued presence of a stimulus. This seems to be counterintuitive, but it
affects anywhere from thirty to fifty percent of all drug receptors and can
occur rapidly within milliseconds to minutes. Wouldn't it be fascinating if the
simple balance also desensitized?
In fact, the balance also desensitizes just like the biological
receptors if the weights are distributed by a Langmuir binding expression,
which is a fundamental chemical expression for calculating molecular binding
(see - Desensitization of a
balance with Langmuir binding of weights. arXiv 2003, http://arXiv.org/abs/physics/0303055).
Perhaps this finding is expected if the chemical balance is being influenced by
the physical binding of the ligands, but it nevertheless seems extraordinary
that such a relatively simple physical system can model some of the most
intractable, nonlinear problems of biological modeling.
Understanding these concepts
with such a simple model, gives us pause to marvel at the fact that we are
allowed to understand such things. We wonder whether this research might also apply to other
mathematical, physical, chemical and biological areas and hope that these
applications will lead to the development of safer pharmaceutical drugs.
Richard Lanzara,
Ph.D.
President and
Principal Scientific Officer
Keywords: GPCRs, Adrenergic,
receptor model, biophysical model, computational model, two-state model,
cysteine, sulfhydryl, thiol, molecular model, acid-base model, mathematical
model, nonlinear, probalistic, drugs, biotech, pharmacology, pharmaceuticals,
receptor activation.