Coal Tar Rational Drug Design

In dermatology, as in many specialties, there are a number of “tried and true” treatments that have been utilized, in some cases for millenia, to treat cutaneous diseases.  These therapies continue to comprise an important part of our therapeutic armamentarium, despite the fact that the mechanisms by which these compounds improve clinical disease courses are often poorly understood.    Modern efforts to understand pathologic disease mechanisms, particularly when undertaken or funded by pharmaceutical companies, tend to focus attention toward the development of novel classes of compounds whose marketing and prescription are likely to be financially lucrative.   Rational drug design describes the concept of designing novel compounds that could structurally or functionally be predicted to modify a pathologic process or target through modification of gene or protein expression (Mandel et al., 2009).  High-throughput computer-based algorithms can be constructed to screen a database of small molecules with unknown targets, or to screen a host of known targets for their potential response to a particular synthesized molecule, to rapidly and efficiently identify potential novel molecule-target combinations.  Similarly, modeling programs can also be used to predict potential toxicities or untoward effects of these novel compounds (Mandel et al., 2009); these potential effects should, of course, then be investigated in experimental settings.

Given the potential for rational drug design methods to identify lucrative novel therapies, much less attention is often paid to gaining a better understanding of the mechanisms of compounds that have been used successfully for hundreds or thousands of years.  Studies undertaken to elucidate the mechanisms by which these therapies exert their actions, however, represent valuable opportunities both to better understand their biological effects and to provide insight into physiologic processes that underlie the diseases these compounds affect.  A recent study published in the Journal of Clinical Investigation provides a fine example of such work (van den Bogaard et al., 2013).  The authors describe a mechanism by which coal tar, via activation of the aryl hydrocarbon receptor (AHR), restores epidermal barrier protein expression and attenuates Th2-cytokine-mediated effects in both in vitro models and in vivo in atopic dermatitis (van den Bogaard et al., 2013).  A commentary in the same issue discusses that although coal tar is comprised of a wide variety of compounds that are likely to have effects on multiple targets in diseases like atopic dermatitis, a better understanding of known biological targets could allow for the extraction of specific active ingredients from coal tar which would hopefully allow for the creation of “cleaner” preparations that would allow patients to refrain from applying sticky, smelly, and stain-inducing coal tar to the skin (McLean and Irvine, 2013).  Identification of new targets (like the AHR) in atopic dermatitis could also guide rational drug design methods to identify or construct novel compounds that could be added to the therapeutic armamentarium.  These articles remind us that despite the current exciting climate of “smart” drug design, which has enabled the rapid introduction of new classes of therapeutic agents that revolutionize the way we treat various cutaneous diseases, we should not entirely neglect the study of “tried and true” therapies – there is likely a very good reason we use them, even if we don’t yet know what that reason is.

 

 

References

Mandel S, Moudgil M, Mandal S (2009) Rational drug design. Eur J Pharmacol 625:90-100.

McLean WHI, Irvine AD (2013) Old King Coal – molecular mechanisms underlying an ancient treatment for atopic eczema. J Clin Invest 123:551-3.

van den Bogaard EH, Bergboer JGM, Vonk-Bergers M, van Vlijmen-Willems IMJJ, van der Valk PGM, Schröder JM, et al. (2013) Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest 123:917-27.

 

 

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