Team develops speedy software designed to improve drug development

Similarly, when a newly created drug doesn’t bind well to its intended target, the drug won’t work. Scientists are then forced to go back to the lab, often with very little indication about why the binding was weak. The next step is to choose a different pharmaceutical “combination” and hope for better results. Georgia Tech researchers have now generated a computer model that could help change that blind process.

Symmetry-adapted perturbation theory (SAPT) allows scientists to study interactions between molecules, such as those between a drug and its target. In the past, computer algorithms that study these noncovalent interactions have been very slow, limiting the types of molecules that can be studied using accurate quantum mechanical methods. A research team headed by Georgia Tech Professor of Chemistry David Sherrill has developed a computer program that can study larger molecules (more than 200 atoms) faster than any other program in existence. 

“Our fast energy component analysis program is designed to improve our knowledge about why certain molecules are attracted to one another,“ explained Sherrill, who also has a joint appointment in the School of Computational Science and Engineering. “It can also show us how interactions between molecules can be tuned by chemical modifications, such as replacing a hydrogen atom with a fluorine atom.  Such knowledge is key to advancing rational drug design.”

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Computer Program Quickly Analyzes Molecular Interactions II

The algorithms can also be used to improve the understanding of crystal structures and energetics, as well as the 3D arrangement of biological macromolecules. Sherrill’s team used the software to study the interactions between DNA and proflavine; these interactions are typical of those found between DNA and several anti-cancer drugs. The findings are published this month in the Journal of Chemical Physics.

Rather than selling the software, the Georgia Tech researchers have decided to distribute their code free of charge as part of the open-source computer program PSI4, developed jointly by researchers at Georgia Tech, Virginia Tech, the University of Georgia and Oak Ridge National Laboratory.  It is expected to be available in early 2012.

“By giving away our source code, we hope it will be adopted rapidly by researchers in pharmaceuticals, organic electronics and catalysis, giving them the tools they need to design better products,” said Sherrill.

Sherrill’s team next plans to use the software to study the noncovalent interactions involving indinavir, which is used to treat HIV patients.

Provided by Georgia Institute of Technology (news : web)

E. coli metabolism reversed for speedy production of fuels, chemicals

In a biotechnological tour de force, Rice University engineering researchers this week unveiled a new method for rapidly converting simple glucose into biofuels and petrochemical substitutes. In a paper published online in Nature, Rice's team described how it reversed one of the most efficient of all metabolic pathways -- the beta oxidation cycle -- to engineer bacteria that produce biofuel at a breakneck pace.

Just how fast are Rice's single-celled chemical factories? On a cell-per-cell basis, the bacteria produced the butanol, a biofuel that can be substituted for gasoline in most engines, about 10 times faster than any previously reported organism.

"That's really not even a fair comparison because the other organisms used an expensive, enriched feedstock, and we used the cheapest thing you can imagine, just glucose and mineral salts," said Ramon Gonzalez, associate professor of chemical and biomolecular engineering at Rice and lead co-author of the Nature study.

Gonzalez's laboratory is in a race with hundreds of labs around the world to find green methods for producing chemicals like butanol that have historically come from petroleum.

"We call these 'drop-in' fuels and chemicals, because their structure and properties are very similar, sometimes identical, to petroleum-based products," he said. "That means they can be 'dropped in,' or substituted, for products that are produced today by the petrochemical industry."

Butanol is a relatively short molecule, with a backbone of just four carbon atoms. Molecules with longer carbon chains have been even more troublesome for biotech producers to make, particularly molecules with chains of 10 or more carbon atoms. Gonzalez said that's partly because researchers have focused on ramping up the natural metabolic processes that cells use to build long-chain fatty acids. Gonzalez and students Clementina Dellomonaco, James Clomburg and Elliot Miller took a completely different approach.

"Rather than going with the process nature uses to build fatty acids, we reversed the process that it uses to break them apart," Gonzalez said. "It's definitely unconventional, but it makes sense because the routes nature has selected to build fatty acids are very inefficient compared with the reversal of the route it uses to break them apart."

The beta oxidation process is one of biology's most fundamental, Gonzalez said. Species ranging from single-celled bacteria to human beings use beta oxidation to break down fatty acids and generate energy.

In the Nature study, Gonzalez's team reversed the beta oxidation cycle by selectively manipulating about a dozen genes in the bacteria Escherichia coli. They also showed that selective manipulations of particular genes could be used to produce fatty acids of particular lengths, including long-chain molecules like stearic acid and palmitic acid, which have chains of more than a dozen carbon atoms.

"This is not a one-trick pony," Gonzalez said. "We can make many kinds of specialized molecules for many different markets. We can also do this in any organism. Some producers prefer to use industrial organisms other than E. coli, like algae or yeast. That's another advantage of using reverse-beta oxidation, because the pathway is present in almost every organism."

Provided by Rice University (news : web)