Researchers' method to rank molecules may aid in search for new drugs.
COLOR ME DRUGLIKEIn
charting the “drug-likeness” of related compounds (represented as
dots), a few tight clusters (left) indicate chemical similarity.
Smaller, dispersed bunches and free-floating dots (right, for a
different type of compound) indicate a lot of chemical variation. The
redder the dots, the closer the compounds are to a QED value of 1,
meaning they are the most druglike. G.R. Bickerton et al/Nature Chemistry 2012
A
new method for rating the attractiveness of a compound could help
chemists discern potential new drugs from duds. Researchers have come up
with a way to quantify a compound’s drug potential that moves beyond
simply “hot or not,” instead providing a measure that allows compounds
to be ranked as well.
The approach “takes things a step further,
looking at multiple factors instead of yes/no,” says chemical
informaticist David Wild, of the Indiana University Bloomington, who
was not involved with the research.
The new technique uses eight
molecular properties — such as the number of rotatable bonds a molecule
has — that influence things like a compound’s toxic effects or its
likelihood of being absorbed in the body. With some clever math, those
probabilities are turned into a number between zero and one. When
researchers tested their method against existing techniques for
screening compounds, it outperformed the standard approaches at
distinguishing known drugs from other molecules, the team reports in the
February issue of Nature Chemistry.
And because the
new method, called QED, or quantitative estimate of drug-likeness,
provides a numerical rating, it allows chemists to prioritize molecules
for drug development, says study leader Andrew Hopkins, an expert in
drug discovery and molecular design at the University of Dundee in
Scotland.
Existing screening techniques are often used to make
pass/fail judgments on compounds’ drug potential. Lipinski’s famous Rule
of Five, for example, which uses measures such as a molecular mass not
greater than 500 daltons to evaluate whether a compound might be
absorbed and used by the body, has become a way to filter whole
libraries of compounds even though it was just meant as a guideline,
Hopkins says. This means potential drugs might be routinely screened out
before they’re even given a chance.
Some chemists actually aim
to break the rules, with the hope of finding a drug no one has bothered
to look at, a sound approach given that 16 percent of today’s oral
medicines —including some well-known drugs — violate at least one of
Lipinski’s rules.
“Our metric suggests you can break some rules,”
says Hopkins. “As with people, you can tolerate some bad behavior in
someone’s personality if they are very good in their other qualities.”
In
addition to assessing 771 oral drugs approved by the Food and Drug
Administration, the researchers used QED to evaluate molecular
properties of drug targets, the binding sites in the body that drugs
latch onto. Since QED evaluates compounds on a continuum, it can reveal
whether some targets’ chemical traits make them harder to get to than
others, potentially highlighting the need for an innovative attack
method.
QED also compared favorably with the gestalt assessment
of chemists. Hopkins and his colleagues compared their technique’s
evaluation of molecules with the opinions of 79 chemists who were asked
whether they would pursue a potential compound. The QED values for both
attractive and unattractive compounds were in line with the chemists’
ratings, suggesting the method nicely eyeballs a compound’s potential
drug-worthiness.
“Chemists do have a concept of good, bad and ugly compounds,” says Hopkins.
The
number of potential compounds and targets is far too large, however,
for chemists to consider one-by-one. Perhaps QED can lend a hand, Wild
says. “Chemists never like being told what to do by a computer, but at
least the computer can help them test ideas.”
0 comments:
Post a Comment