By Brian K. Shoichet
ESI Special Topics,
September 2003
Citing URL - http://www.esi-topics.com/nhp/2003/september-03-BrianKShoichet.html
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Brian K. Shoichet answers a few questions about this month's
new hot paper in the field of Chemistry.
From
•>>September 2003
Field:
Chemistry
Article Title:
"A common mechanism underlying promiscuous inhibitors
from virtual and high-throughput screening"
Authors: McGovern, SL;Caselli, E;Grigorieff, N;Shoichet, BK
Journal: J MED CHEM
Volume: 45
Page: 1712-1722
Year: APR 11 2002
* Northwestern Univ, Dept Mol Pharmacol & Biol Chem, 303 E Chicago Ave, Chicago, IL 60611 USA.
* Northwestern Univ, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA.
* Brandeis Univ, Rosenstiel Basic Med Res Ctr, Howard Hughes Med Inst, WM Keck Inst Cellular
Visualizat, Waltham, MA 02454 USA.
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 Why
do you think your paper is highly cited?
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 This paper is highly cited because it argues that there is such a common mechanism--aggregation of the organic molecule--and once we made this suggestion it brought coherence to many observations in the field, and in some sense fit in with the intuition of many investigators.
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The paper describes a single,
common mechanism underlying promiscuous inhibition of enzymes by
many organic, "drug-like" molecules: aggregation of the
organic molecules into large (~200 nm) particles, which then
sequester and inhibit enzymes non-specifically. Promiscuous
(non-specific) inhibition is a huge problem in high-throughput
screening (HTS), which is the dominant technique for discovering new
leads in drug design. What investigators have found, repeatedly, is
that a large proportion of their "hits" from HTS act
strangely and are promiscuous. A large literature has grown up
around trying to predict what molecules would behave this way, but
until this paper came out I don't think anyone had considered, at
least in print, that there may be a common, essentially
physical-chemical explanation for this behavior. This paper is
highly cited because it argues that there is such a common mechanism—aggregation
of the organic molecule—and once we made this suggestion it
brought coherence to many observations in the field, and in some
sense fit in with the intuition of many investigators.
Does
it describe a new discovery or a new methodology that's useful to
others?
Both a new discovery, aggregation of the organic molecule
leading to promiscuous inhibition, and a methodology to detect and
discard molecules that act this way. Subsequent papers have
explored developing rapid assays to detect these aggregates,
which may find wide use in HTS.
Could
you summarize the significance of your paper in layman's terms?
High throughput screening (HTS) is the dominant method to
discover novel molecules that might be developed into drugs. This
technique tests large libraries of molecules, maybe half a
million, very rapidly against an enzyme or receptor implicated in
disease. A problem with HTS is that many of the molecules that it
finds don't have much specificity for the target; they inhibit
lots of things. This would be an unfavorable feature for a drug,
since it would likely have lots of side effects, among other
problems. Thus these "promiscuous" hits are eventually
discarded, typically after a lot of (wasted) follow up work. What
we found is that a single, physically-understandable mechanism
explains the actions of many of these "promiscuous"
inhibitors—they first aggregate into large particles in
solution, and it is the aggregated particles that inhibit many
enzymes. In retrospect, this mechanism explains the actions of
many "promiscuous" molecules that have been found over
the years. The significance is that, with this mechanism in mind,
these "promiscuous" molecules can be found early and
discarded, allowing effort to be focused on the truly interesting
new molecules coming out of drug discovery efforts.
How
did you become involved in this research?
It happened by accident. We were trying to discover novel
inhibitors of an antibiotic resistance enzyme, beta-lactamase, and
we had a lot of "hits." When we looked closely at them,
however, they turned out to be non-specific and have strange
kinetic profiles. We kept throwing these "pathological"
inhibitors out and looking for new ones, but we just kept finding
more "pathologicals." This was incredibly frustrating.
Eventually we became so frustrated that we decided to try and find
out, in detail, what was going on with these molecules.
Fortunately for me, I had a talented—not to mention courageous—graduate
student in the lab, Susan McGovern, who agreed to take the project
on. It turned out to be enormously exciting, but at the beginning
there were some dark days when we were baffled.
Brian Shoichet
Department of Pharmaceutical Chemistry
University of California, San Francisco
San Francisco, CA, USA
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ESI Special Topics,
September 2003
Citing URL - http://www.esi-topics.com/nhp/2003/september-03-BrianKShoichet.html
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