Drug Discovery with Computational Chemistry


Unhappy water: Chemical modeling software called WaterMap can predict how water molecules, shown here in red and green, can influence how strongly drug candidates bind to their intended target.     Credit: Schrödinger




A startup is banking on new software that incorporates the energy of water molecules into chemical models




MIT Technology Review, July 20, 2011, by Emily  Singer  —  Most pharmaceutical companies use software to model chemical interactions, with the hope of speeding up the drug development process. But it’s typically a small component of a complex array of approaches. Nimbus Discovery, a startup based in Cambridge, Massachusetts, is using computational chemistry to drive the entire process.

The company emerged from a partnership with Schrödinger, a maker of computational drug discovery software, and venture capital firm Atlas Venture. Nimbus will use Schrödinger’s software, computing power, and modeling experts to develop drugs for disease-linked proteins that have historically been difficult to target.

If successful, this computationally driven approach could make drug development faster and cheaper by making much of the trial and error process virtual.  Nimbus recently raised $24 million in venture funding. Bill Gates was one of the investors.

Schrödinger’s software, which is used by many pharmaceutical companies, models the various chemical forces that drive a candidate drug molecule to bind to a specific spot on the target protein. That allows drug developers to predict how well various candidate molecules bind to targets of interest. While this approach has been in use for about two decades, it has yet to truly transform the drug-discovery process.

Nimbus researchers think that part of the reason is that most tools fail to incorporate the thermodynamics of the resident water molecules in the protein’s binding site. “The need for improved water models is a widely acknowledged yet seldom-addressed limitation of current methods,” says Christopher Snow, a postdoctoral researcher at Caltech who is not involved with the company. It’s difficult to model the energy of water molecules.

WaterMap, a new tool from Schrödinger that predicts how water will affect the binding reaction, could overcome that barrier. “We think we can use our technology to transform the way drug development is done,” says Ramy Farid, president of Schrödinger and cofounder of Nimbus. Researchers have used WaterMap to explain the success or failure of some molecules, as well as to develop new candidate molecules. “It led in a number of cases to rapid development of drug candidates that were of higher quality than what appeared to be otherwise possible,” says Farid.


The startup spent its first year using the software to narrow down a list of 1,200 potential drug targets, chemical binding sites on different disease-linked proteins, to a list of 20 that looked most amenable to the technology. (That depended on a number of factors, including knowledge of the protein’s three-dimensional structure, its desirability as a target for disease, as well as the number of water molecules that reside in the binding site.) The company will focus on targets involved in inflammation, oncology, metabolic disease, and antibiotics.

The most advanced target to date is called IRAK4, a kinase enzyme that plays a role in inflammation and drives an aggressive form of non-Hodgkin’s lymphoma. Researchers conducted a virtual drug screen, looking for molecules that would bind to IRAK4, and then put those virtual molecules to the test by synthesizing them and running real chemical reactions. “We have been able to quickly find a highly selective molecule with drug-like properties,” says Rosana Kapeller, Nimbus’s chief scientific officer. It took just nine months to go from virtual screening to testing in animal models of disease.

“We have seen powerful examples of how minor changes to the molecule can result in profound changes in binding,” says Bruce Booth, one of Nimbus’s cofounders. By displacing one “unhappy” molecule, a high-energy water molecule in the binding site, “we can improve binding a hundred-fold,” he says.

While WaterMap is available to pharmaceutical companies for purchase, Farid says, the newness of the technology, and the fact that it requires intense computing power, has made it difficult to implement effectively. Part of the reason for founding Nimbus, he says, was to demonstrate how powerful the tool can be.

But it remains to be seen how significantly the WaterMap tool will speed drug discovery or how broadly applicable it will be. It may turn out to be very useful for some targets but not others.


Cell rebirth: Charles Limoli hopes that neural stem cells, like the ones shown here, can help regenerate brain cells damaged or destroyed by cancer treatment. Cell nuclei are shown in red.    Credit: Charles Limoli




The study could offer hope for brain cancer patients, who often suffer dire cognitive problems as a result of radiation treatment




MIT Technology Review, July 20, 2011, by Karen Weintraub  —  Radiation treatment for brain cancer can be lifesaving, but it can come at a terrible cost. The radiation that kills cancer cells also kills brain cells, destroying memories, impairing intelligence, and causing confusion.

Charles Limoli and colleagues at the University of California, Irvine, have shown that stem cells could help reverse some of this damage. In a new paper in the journal Cancer Research, Limoli shows that it’s possible to cause new brain cells to grow by injecting human neural stem cells into the brains of mice whose cognitive abilities had been damaged by radiation. The mice regained lost skills after the stem-cell treatment.

Stem cells have long been used to repair the damage caused by cancer treatment. Bone-marrow transplants for leukemia rely on stem cells to replenish blood cells, for instance. But Limoli says his team is the only one using neural stem cells to treat symptoms in the brain.

Several peers praised his work, calling it an important proof of the idea that human stem cells can repair neuronal damage.

“The results are very promising,” says Howard B. Lieberman, professor of radiation oncology and environmental health sciences at Columbia University. “If the findings continue to be as positive as what’s published in this paper, I would assume Dr. Limoli will take great effort to try to move it into the clinic as quickly as possible.”

Limoli’s team irradiated three groups of mice, later treating two of them with human neural stem cells. The third, a control group, received a sham surgery, but no cells were implanted. One month after the damage, 23 percent of implanted stem cells were active in the brains of the first group of mice. After four months, 12 percent were still active in the second group. Using cellular labeling, Limoli’s team also showed that tens of thousands of new neurons and astrocyte cells had grown in the brains of the treated mice. The treated mice performed better than the untreated ones on cognitive tests, and recovered their preradiation abilities.

Protein activity in the treated mice suggests that the implanted stem cells are integrating into the brain, Limoli says, replacing cells that have been lost or damaged.

Both Limoli and Lieberman say the treatment could also be effective against “chemo brain,” a side effect often reported by breast cancer patients. The chemotherapy can impair their ability to focus and think clearly.

Rob Coppes, a radiation and stem-cell biologist at the University Medical Center Groningen, in the Netherlands, says he would next like to see Limoli test how long the benefits of the stem cells last. He also hopes Limoli will repeat his experiments using induced pluripotent stem cells (iPS cells), adult stem cells that have been converted back to an embryonic-like state. These would likely be the cells that doctors would use in patients. Ideally they’d be taken from the patients themselves to avoid an immune rejection.

It will be important to show that mice—and later, humans in a trial—don’t reject these cells, and also that the stem cells don’t trigger new cancers, says Coppes, who employs stem cells in his own work, which involves regenerating salivary glands.

Limoli plans to carry out further work involving human neuronal stem cells and iPS cells. He also wants to figure out the optimal time to transplant these stem cells into the brain.


Credit: Technology Review




A study says that we rely on external tools, including the Internet, to augment our memory



MIT Technology Review, July 20, 2011, by Kenrick Vezina  —  The flood of information available online with just a few clicks and finger-taps may be subtly changing the way we retain information, according to a new study. But this doesn’t mean we’re becoming less mentally agile or thoughtful, say the researchers involved. Instead, the change can be seen as a natural extension of the way we already rely upon social memory aids—like a friend who knows a particular subject inside out.

Researchers and writers have debated over how our growing reliance on Internet-connected computers may be changing our mental faculties. The constant assault of tweets and YouTube videos, the argument goes, might be making us more distracted and less thoughtful—in short, dumber. However, there is little empirical evidence of the Internet’s effects, particularly on memory.

Betsy Sparrow, assistant professor of psychology at Columbia University and lead author of the new study, put college students through a series of four experiments to explore this question.

One experiment involved participants reading and then typing out a series of statements, like “Rubber bands last longer when refrigerated,” on a computer. Half of the participants were told that their statements would be saved, and the other half were told they would be erased. Additionally, half of the people in each group were explicitly told to remember the statements they typed, while the other half were not. Participants who believed the statements would be erased were better at recalling them, regardless of whether they were told to remember them.

Another experiment had subjects again typing predetermined statements into a computer, but this time, some were told that their statements would be saved in a specific folder on that machine. Participants were better at remembering the names of the folders a statement was stored in than they were at remembering the statements themselves.

The experiments suggest that we are less likely to remember facts when we know they can be easily looked up online, the researchers say. This conclusion is an extension of an idea proposed some 30 years ago by Sparrow’s mentor (and a coauthor of a paper describing the latest work), Daniel Wegner, of Harvard’s psychology department.

Wegner proposed the idea of “transactive memory” as a collective social memory of sorts. For example, if a friend has an exhaustive knowledge of Greek history, you can simply remember that The Iliad is Greek and that your friend knows about Greek things, rather than remembering who wrote the epic poem. Sparrow and Wegner say that the Internet may serve a similar function, acting as an extension of this external memory.

Mary C. Potter, professor of psychology in MIT’s Department of Brain and Cognitive Sciences, says the study supports the commonsense idea that we use external tools to remember information. She notes, however, that many of the results are at the threshold for statistical significance, and says the study should be seen as suggestive rather than conclusive.

Potter also wonders if the results may be due to sociological rather than psychological phenomena. When your friend whips out his smart phone to look up information about a band, this could be “because it’s fun” rather than being about changes to how our brains store information, she says.

Nicholas Carr has been one of the leading voices in the debate. His book The Shallows, published in June, contends that the Internet is having a detrimental effect, an argument he supports with numerous scientific studies. He says Sparrow’s study “indicates how flexible our brains are in adapting to our tools.”

However, he’s not convinced that this adaptation is positive. “It’s critically important to remember that there’s a difference between external memory and internal memory,” he says. “If you’re not internalizing … then your understanding becomes less personal, less distinctive, and, I think, ultimately more superficial.”

Sparrow, on the other hand, sees this adaptation as positive. She says our minds are molding to the Internet, just as they have in the past with technologies like the written word.

She’s now trying to probe the benefits of this external memory with more experiments. Imagine a history student reading a dense passage, full of dates and names, about the American Revolution. Perhaps if the student is confident that the details will be available on the Internet, he will be better able to get a larger sense of why the revolution happened. Her intuition is that when we expect the details to be available later, we’re better at looking for larger messages that might be obscured if we were preoccupied with minutiae.