Drug design: New book introduces fresh approach

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Drug design: New book introduces fresh approach
Rice professor says drug industry can improve drug safety, lower costs

The pharmaceutical industry can reduce costs, bring new drugs to market
more quickly and decrease the dangerous side effects of new medications
if it pays closer attention to the latest research regarding the subtle
differences between closely related protein targets.

	ARIEL FERNANDEZ

A new book, “Transformative Concepts for Drug Design: Target Wrapping”
(Springer) by Rice University bioengineering professor Ariel Fernandez,
suggests new methods the industry can use to improve its bottom line
today. The same methods could also usher in an era of personalized
medicine by allowing drugmakers to identify idiosyncratic differences
among individuals and to tailor drugs for patients.

“The
industry is at a crossroad,” said Fernandez, Rice’s Hasselmann
Professor of Bioengineering. “The old way of finding therapeutic
compounds by trial and error is playing out. Genomics has revealed the
protein targets for many major diseases, but current methods of drug
discovery are often hopelessly inadequate for the task of attacking
these targets.”

Fernandez said it takes about a decade and costs
about $1 billion to bring a new drug to market, and the lead time and
costs for drug development are increasing.

When the human genome
was sequenced a decade ago, many believed it would lead to an era of
“rational” drug design in which drugmakers would create drugs molecule
by molecule. But rational drug design hasn’t panned out, largely
because scientists still don’t understand the fundamental biophysical
principles that govern how drug molecules interact with proteins,
Fernandez said.

“Proteins come in families, and the members of
these families, or paralogs, can be almost identical,” he said. “It is
very difficult to find a compound that will selectively target one
paralog without targeting the others.”

For
example, blocking the protein called “focal adhesion kinase,” or FAK,
has been shown to decrease the risk of metastasis of some types of
cancer. But a standard structural analysis shows that FAK is nearly
identical to the protein that insulin molecules use to dock with cells.
Designing a drug that blocks FAK and does not block the insulin
receptor signaling on cells has proven extremely difficult.

The
similarities between proteins that are linked with diseases and those
that are crucial for healthy function in other parts of the body are
the underlying cause for the side effects of drugs.

A crucial
proof of concept for the innovative remedial approaches proposed in the
book came in 2007. Fernandez said that at that time, he and colleagues
from the University of Texas M.D. Anderson Cancer Center used the new
methods to re-engineer the powerful anticancer drug imatinib — best
known by its brand name Gleevec — to more specifically target one type
of cancer while curbing a rare life-threatening cardiotoxic side effect.

The
redesigned drug is identical to imatinib, save for the addition of four
atoms at a key point. Though the change is minimal, it allows the drug
to effectively target cancer-related proteins without affecting similar
proteins in heart cells.

“Almost all proteins have minor defects
or structural deficiencies that leave some of their hydrogen bonds
poorly shielded from water,” Fernandez said. “These incompletely
wrapped bonds, which I termed dehydrons, differ even between closely
related protein paralogs, and drugmakers can use them as the basis for
re-engineering drugs to be more selective.”

Fernandez said many
potential drug compounds are effective disease fighters but are dropped
during late-stage trials — and at great cost — because of toxic side
effects. Re-engineering such compounds could save drugmakers a fortune
in research and development costs.

“This is not a de novo
rational drug design,” he said of the re-engineering method. “It
extends the tried-and-true drug discovery methods industry is
comfortable with, but it does this in a rational way that will save
R&D costs, reduce toxic side effects and ultimately increase the
safety of molecular targeted therapy.”