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Exploring Rational Drug Design

Medicinal chemists strive to optimize molecules that fit snugly into their proposed targets. But in the quest for potency, we often overlook the local physics that govern drugs’ binding to these receptors. What if we could rationally predict which drugs bind well to their targets?

A new review, currently out on J. Med. Chem. ASAP

, lays out all the computational backing behind this venture. Three computational chemists (David Huggins, Woody Sherman, and Bruce Tidor) break down five binding events from the point-of-view of the drug target: Shape Complementarity, Electrostatics, Protein Flexibility, Explicit Water Displacement, and Allosteric Modulation….whew!

Selectivity Strategies

Selectivity Strategies for Rational Design | Credit: Huggins, Sherman, Tidor; J. Med. Chem.

Note: Before we dive into this article, let’s clarify a few terms computational drug-hunters use that bench chemists think of differently: ‘decoy’ – a test receptor used to perform virtual screens; ‘ligand’ – the drug docking into the protein; ‘affinity / selectivity’ – a balance of characteristics, or how tightly something binds vs. which proteins it binds to; ‘allosteric’ – binding of a drug molecule to a different site on an enzyme than the normal active site. Regular readers and fans of compu-centric chem blogs such as

The Curious Wavefunction and Practical Fragments will feel right at home!

We’ll start at the top. Shape complementarity modeling uses small differences in a binding pocket, such as a methylene spacer in a residue (say, from a Val to Ile swap) to dial-in tighter binding between a target and its decoy. The authors point out that selectivity can often be enhanced by considering a drug that’s literally too big to fit into a related enzymatic cavity. They provide several other examples with a ROCK-1 or MAP kinase flavor, and consider software packages designed to dock drugs into the “biologically active” conformation of the protein.

Electrostatic considerations use polar surface maps, the “reds” and “blues” of a receptor’s electronic distribution, to show how

Affinity Optimization

Affinity Optimization - Black dot represents the optimal minimum energy between Coulombic forces (green) and desolvation penalty (blue) | Credit: Huggins, Sherman, Tidor; J. Med. Chem.

molecular contacts can help binding to overcome the desolvation penalty (the energy cost involved in moving water out and the drug molecule in). An extension of this basic tactic, charge optimization screening, can be used to test whole panels of drugs against dummy receptors to determine how mutations might influence drug binding.

Because target proteins move and shift constantly, protein flexibility, the ability of the protein to adapt to a binding event, is another factor worth considering. The authors point out that many kinases possess a “DFG loop” region that can shift and move to reveal a deeper binding cavity in the kinase, which can help when designing binders (for a collection of several receptors with notoriously shifty binding pockets – sialidase, MMPs, cholinesterase – see p. 534 of Teague’s NRDD review).

But these shifting proteins also swim in a sea of water and other cytoplasmic goodies. This means that drug designers, whether they like it or not, must account for explicit water molecules. The authors even suggest a sort of “on-off” switch for including the bound water molecules, but contend that more efforts should be directed to accurate modeling of water in these protein settings.

Finally, the authors weigh the effects of allosteric binding, the potential for a modeled molecule to be highly selective for a site apart from where the protein binds its native ligand. The authors consider the case of a PTP1B ligand that binds 20Å away from the normal active site, at the previously mentioned “DFG loop.” Since this binding hadn’t been seen for related phosphatases, it could then be used to control selectivity for PTP1B.

In each section, the authors provide examples of modeling studies that led to the design of a molecule. Two target classes recur oftenCOX and HIV inhibitors throughout the review: HIV protease inhibitors (saquinavir, lopinavir, darunavir) and COX-2 inhibitors (celecoxib), which have all been extensively modeled.

Two higher-level modeling problems are also introduced: the substrate-envelope hypothesis, which deals with rapidly mutating targets, and tailoring molecules to take rides in and out of the cell using influx and efflux pumps in the membrane. Since different cell types overexpress certain receptors, we can use this feature to our advantage. This strategy has been especially successful in the development of several cancer and CNS drugs.

Overall, the review feels quite thorough, though I suspect regular Haystack readers may experience the same learning curve I did when adapting to the field-specific language that permeates each section. Since pictures are worth a thousand words, I found that glancing through the docking graphics that accompany each section helped me gain a crucial foothold into the text.

Chemistry Romance Novel Drops Feb. 7

Courtesy of Heather Snow

Have too many long nights in the lab left you without a special someone this Valentine’s Day? Has grant writing drained all the spark from your relationship?

Well, debut author Heather Snow’s novel, “Sweet Enemy,” might be just the thing to push you over the activation barrier, if ya’ know what I mean. Snow’s book, available online and in bookstores February 7, is a historical romance novel with a chemist heroine.

Avid Newscripts readers may recall C&EN’s 2010 profile of Snow, when her then-manuscript Sweet Enemy was a finalist for a Golden Heart Award, essentially the Oscars of the romance novel world.

Since then, Snow, who majored in chemistry at the University of Missouri, Kansas City, has moved up in the romance novel world, selling her manuscript and launching a monthlong blog book tour to promote Sweet Enemy.

Snow sent Newscripts the book’s cover–a rendering of heroine Liliana Claremont, orphaned daughter of a well-known chemist. “No cool glassware,” she says. “But they did give her a quill and ink to make her look ‘smart.’ ”

Snow has also made the book’s prologue and first chapter available online, so you can find out how Liliana uses her scientific smarts to outwit an intruder.

From there, the drama kicks into high gear. But the heroine does get a happy ending. Snow let slip that Liliana’s hero proposes not with a diamond ring, but with a matrass–a round-bottomed flask with a long, slender neck, commonly used for distillations among Liliana’s 19th-century contemporaries. Clearly her lover knew the way to a chemist’s heart.

How Jagabandhu Das made dasatinib possible

In my story on how drugs get their generic names for this week’s issue of C&EN, I briefly discussed how the chronic myelogenous leukemia medication Sprycel (dasatinib), mentioned in this Haystack post by SeeArrOh, ended up being named after Bristol-Myers Squibb research fellow Jagabandhu Das. Even though Das, or Jag, as his coworkers call him, didn’t discover the molecule that bears his name, the program leader for Das’s team, Joel Barrish, says dasatinib wouldn’t have existed without him.

So how’d Das make a difference? About one and a half years into the search for a kinase inhibitor that might be able to treat chronic myelogenous leukemia, “we were hitting a wall,” Barrish, today vice-president of medicinal chemistry at BMS, recalls. “We couldn’t get past a certain level of potency.”

Early on, the team’s work suggested that a 4′-methyl thiazole was critical for potency. Replace the methyl with a hydrogen, and potency went out the window. But Das challenged that dogma, Barrish says. He thought the compound series had evolved to the point where it would be a good idea to go back and test those early assumptions. His hunch paid off– in the new, later kinase inhibitor series, it turned out that removing the methyl group from the thiazole actually boosted potency. Thanks in large part to that discovery, the team eventually was able to make kinase inhibitors with ten thousand fold higher activity.

Dasatinib (J. Med.Chem.)

“Jag didn’t stop there,” Barrish says. After debunking the methyl dogma, Das found a way to replace an undesirable urea moiety in the team’s inhibitors with a pyrimidine group, which improved the inhibitors’ physical properties. With help from Das’s two insights combined, eventually BMS’s team came up with the molecule that became dasatinib (J. Med. Chem., DOI: 10.1021/jm060727j).

Generic naming requirements are extensive, but the committees involved in the naming process are willing to use inventors’ names as long as they fit the criteria.
But sometimes, Barrish says, “there’s luck involved in who makes the final compound.” In the dasatinib story, though, it was clear that Das’s discoveries were the keys to success.

When dasatinib was in clinical trials and it came time to put forward a set of possible generic names for consideration, Barrish didn’t have to think too hard about who was most responsible for his team’s success. “It was very clear in my mind that it was Jag,” he says. So he added dasatinib to the list.

“I admit, it was one of those things you do and you kind of forget about it, thinking, ‘oh, they’ll pick something else’,” Barrish says. When dasatinib ended up being the name of choice, he says, it made the entire team feel good. “And obviously, Jag was quite pleased with it.”

The HCV Combo Race Just Got Hotter

BMS is shelling out $2.5 billion dollars for Inhibitex, a small pharma company with a Phase II molecule for treatment of Hepatitis C (HCV). The deal adds to the scramble for HCV assets in recent months, with Gilead agreeing to pay almost $11 billion for Pharmasset in November, and Roche’s recent purchase of Anadys. While much has been written about the merits (and price tags) of each deal, the Haystack thought it was worth taking a closer look at the chemical composition of the multi-million dollar molecules.

So what did BMS get for their money?

INX-089, Inhibitex’s lead molecule, has a common antiviral motif: a nucleoside core (the 5-membered ring sugar attached to a nitrogen heterocycle) with an amino acid based prodrug hanging off the left-hand side. Clinically-tested antivirals sharing this basic setup include IDX-184 and NM-283, both from Idenix, and PSI-352938, from Pharmasset  (For an overview of the varied structures currently in development for HCV, see Lisa’s 2010 C&EN story).

INX-089 bears a close resemblance to Pharmasset’s lead nucleotide inhibitor PSI-7977. That’s not a mistake, believes ‘089 discoverer Chris McGuigan, of the Welsh School of Pharmacy. In a recent article (J. Med. Chem. 2010, 53, 4949), McGuigan himself comments “The Pharmasset nucleoside [is] rather parallel to our early work on anti-HIV ProTides.”

Wait, what are ProTides?

Both INX-089 and PSI-7977 aren’t themselves the active viral inhibitor, but phosphoramidate “ProTide” prodrugs: compounds broken down by the body into the active drug (Chem Note: PSI-7977 has single-enantiomer Sp chirality at phosphorus, while INX-189 is a mixture of diastereomers).

Once in the body, enzymes cleave the phosphoramidate group to a phosphate (PO42-). Kinases attach two more phosphate groups, and viruses let this dressed-up molecule inside, where the nucleotide warhead inhibits HCV by interfering with RNA replication (Antimicrob. Agents Chemother. 2011, 55, 1843).

A few comments on the drug itself: The similarity of the ProTide portion (left-hand side) of the molecule to PSI-7977 really is striking: swap in an isobutyl ester and a phenyl, and it’s the same beast! The more interesting switch comes on the upper-right (“eastern”) part of the structure: a protected guanosine ring. This ring harks back to guanine, one of the four common nucleic acids found in DNA.

Source: J. Med. Chem., Pharmasset

PSI-7977, meanwhile, shows off a uracil, a nucleic acid found in RNA, not DNA.

Although it’s tempting to think such similar compounds all dock into the NS5B polymerase at the active site (in the yellow “palm” of the hand-shaped enzyme), don’t be too sure – a recent paper by Pharmasset scientists (J. Med. Chem. 2012, Just Accepted) shows quite a few “Finger,” “Palm,” and “Thumb” sites.  It’s not yet clear whether all nucleoside drugs bind to the active site in the same way. The authors also remark that, due to fast replication and mutation, potentially resistant strains of HCV pop up daily.

On Birth Control,“Plan B,” and…Batman

The “morning-after” pill, used to prevent conception when other planning methods fail, became a political lightning rodlevonorgestrel this week. Reports by Pharmalot, NPR, Reuters, and many others relate how the Secretary of the U.S. Department of Health and Human Services blocked an FDA recommendation to provide over-the-counter access to this treatment to a wider range of patients (currently, women under the age of 17 must have a prescription to obtain Plan B).

After the uproar generated by the announcement, I wondered what, exactly, was this contentious molecule, and what did it do?

In the US, hospitals administer Plan B as two small pills, each with a 750 μg dose of the synthetic hormone levonorgestrel. First approved by the FDA in 1999, levonorgestrel prompted several companies, among them generic manufacturers Barr, Watson, and Teva, to jump in as suppliers in the ensuing decade. According to a 2011 Teva patent, Plan B is most effective when taken within 72 hours of when a person’s first-line contraceptive fails. The FDA estimates its success rate at 80-90%.

Levonorgestrel binds to the same receptors as other sex hormones (think estradiol or progesterone), and prevents ovulation or impairs fertilization of egg cells. Some researchers believe that Plan B prohibits already-fertilized eggs from adhering to the endometrium (uterine inner wall), which might prevent further embryonic development leading to pregnancy. In fact, a large dose of 17-α-ethinylestradiol (EE) – the main ingredient in most birth control pills – can sometimes be used “off-label” to achieve the same effect.

DESThe uncertainty over whether Plan B actually terminates pregnancies brings it onto similar ground with mifepristone (RU-486) and diethylstilbestrol (DES). These two drugs, previously popular options for emergency contraception, have mixed public perception today; many associate RU-486 with abortion, and DES with endocrine disorders and tumor formation in offspring.

Chemistry Note: It’s humbling to watch Mother Nature re-use the same chemical templates over and over, and that small changes in the overall steroid structure lead to huge biochemical consequences. Like Batman, with his never-ending supply of utility-belt gadgets, the steroid core structure can be tweaked in seemingly endless ways to produce biologically active molecules. I would have to devote (several) more posts to just how many modifications, but think about the effects simple oxidation (bile acids), ring expansion (cortistatins), or conjugation (sulfonated sterols) have on biological processes.


The sex hormones have been puzzling synthetic chemists for nearly 100 years; in fact, two prominent chemists spent large portions of their careers perfecting the introduction of a single methyl group into the steroid core! Levonorgestrel claims “second-generation” hormone status; next-gen progestins, such as desogestrel, do away completely with C-3 oxygenation, and sport a new alkene at C-11. These new atomic decorations lead to improved side-effect profiles and lower the overall EE dose in combined pill formulations.

Update (6:05PM, Dec 9, 2011) – Changed “mg” to “μg”  (Thanks, Ed!) 

Will It Blend?

In this week’s print Newscripts column, I wrote about Will It Crush? That’s a project launched by oceanographer Matthew Alford of the University of Washington, Seattle, to educate kids about what it’s like at the bottom of the ocean. Alford, who studies ginormous underwater waves that affect Earth’s climate, takes everyday objects to the depths of the ocean and films what happens to them under the crushing pressure of all that water.

Those poor Gummi bears–they survived, but, man, they got squished.

Alford told me that his project was inspired by the YouTube video series Will It Blend? These clips are put together by Utah-based firm Blendtec to showcase its blenders and have a bit of fun. I’d never heard of the “sensational” YouTube channel before, but I’ve since checked it out and thought I’d share a favorite clip or two to celebrate the fact that it’s Friday.

For the chemists, check out the glow stick reaction in this clip–and kids, don’t try this at home.

Continue reading →

A 3-D Printer In Every Kitchen

In this week’s issue of C&EN, I wrote a story about 3-D printers—those machines that build solid objects one layer at a time–and the materials that scientists are developing for use with the technology. I’ve had a slight obsession with 3-D printing in the past (see here and here for posts about using the machines for creating buildings and identifying the remains of soldiers), but this article, to my delight, allowed me to go “full tilt” on the subject.

Near the end of the story, Cornell’s Hod Lipson, director of the Creative Machines Lab, says that food printing in particular might just be the “killer app” that drives the market for 3-D printers. He likens it to how the demand for faster, more complex, better-looking video games drove the development of personal computing technology. One day, he believes, every person will have a 3-D printer in the kitchen, just like we all have computers in our offices now.

The Creative Machines Lab runs the Fab@home project which released online the blueprints some years ago for a 3-D printer that works by squeezing pastes and slurries out of syringes. The technology relies on the materials to harden in some way after printing. Once the plans for the printer were made open-access in 2007, people began printing various types of food.

To supplement my story this week, I thought I’d share some rad videos of food printing to pique your appetite—for 3-D printers as well as the food they can create.

In the video above, David Arnold, a chef at the French Culinary Institute, in New York, prints masa, a corn-based dough (think tortillas), into neat shapes. He then steams it and fries it for some crunchy goodness. Although Arnold has said on his blog that he fears a future in which 3-D printers are used to print out dinner from a series of homogenous pastes, he thinks that the technology can be useful in some situations. Cookies, for instance. Continue reading →

The Warp And Weft Of Blue Jeans

My significant other’s place of business in Washington, D.C.—Land of The Stuffed Shirts—recently announced that its list of acceptable Casual Friday clothing had expanded to include blue jeans. I’ve never seen so much joy and excitement among government workers over clothing. And it’s all because of the beloved status that the iconic pants have achieved. The average American probably owns at least five pairs of them.

In this week’s issue of C&EN, I wrote a short story about the chemistry that goes into making blue jeans, noting that the cotton yarn used to make denim doesn’t go directly from white to blue during the dyeing process. Interestingly, it passes through a short phase of being yellow. This is because indigo, the dye responsible for blue jeans’ hue, is not soluble in water in its native form. To dye yarn, indigo must be reduced to leucoindigo, white in powder form and yellow when dissolved in a basic solution.

So, when cotton yarn dips into a vat of leucoindigo dye, it comes out yellow, turning blue as oxygen in the air converts the reduced compound into indigo. To see the chemistry in action, click on the video above.

One thing I didn’t have the space to mention in my feature story is that leucoindigo sticks to cotton yarn better when the fibers are pretreated with a strong base such as caustic soda. This is something that indigo dyers often do to yarn before passing it into dye vats. The base swells the cellulose fibers in the cotton and causes them to go from having an alpha structure to a more crystalline, beta structure that has a higher affinity for the dye. This process is called mercerization among textile makers.

Credit: Wikimedia Commons

Once the cotton yarn used to make denim has been dyed, washed, and neutralized, it is coated with starch to strengthen it for weaving. At this point, the dyed threads are called “warp.” When woven into denim, these blue threads run parallel in the fabric and are put together with white cotton “weft” thread, which runs perpendicular. Look down at your jeans, and you’ll see what I mean.

Georg Schnitzer, an indigo expert at the Singapore-based supplier Bluconnection, explained to me that when denim is woven, it is done in such a way that 75% of the material’s blue warp is on the outside of the pants and 75% of the white weft is on the inside. You can check this out as well, the next time you wash your favorite blues.