What Are Your Favorite Non-U.S. Drug Discovery Stories?
Jun18

What Are Your Favorite Non-U.S. Drug Discovery Stories?

Over at my other gig at the Pharma & Healthcare section of Forbes.com, I've been covering a few stories of new drugs and improvements on old drugs. Although I'm focusing on natural products like vancomycin and semi-synthetics like lurbinectedin, I've been thinking a bit about the stories behind the discoveries of all drugs. Part of my thinking has been driven by my current reading of Happy Accidents: Serendipity in Modern Medical Breakthroughs by Morton A. Meyers, MD, professor emeritus of radiology and internal medicine at SUNY–Stony Brook. Therein, I'm reading stories like that of Gerhard Domagk, who first showed that prontosil was an effective antibiotic in vivo but not in vitro because it liberates sulfanilamide when metabolized. The story was told in even greater detail in the superb Thomas Hager book, The Demon Under the Microscope. This got me to thinking: I hear quite a bit about drug discovery stories in the U.S. but rarely about modern drugs that have been discovered elsewhere. The brain tumor drug, temozolomide, for example, was developed in the laboratory of Malcolm Stevens at Aston University building upon work of the late Tom Connors (expertly told by Kat Arney at Cancer Research UK last summer). But one rarely hears stories like these, even in pharmacology courses at pharmacy schools where the teaching is more likely to be chemistry-oriented. So, chemistry world hivemind: What are your favorite stories of drug discovery and development that didn't occur in the United States? Bonus points for natural products or...

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Must-See ACS Webinar: Superbugs and Drug Development
Feb26

Must-See ACS Webinar: Superbugs and Drug Development

One of science journalism's expert voices, author Maryn McKenna, will be the guest on this Thursday's ACS Webinar Joy of Science series at 2:00 - 3:00 pm Eastern time. Free, as always, you can sign up to participate at this link. McKenna's book, SUPERBUG: The Fatal Menace of MRSA, is a thorough and accessible investigation of the reemergence of lethal bacterial infections while new drug development lags. The book, now in paperback, received the 2011 Science in Society Award from the the National Association of Science Writers. McKenna had spent much of her career at the Atlanta Journal-Constitution as the only U.S. reporter assigned full time to the Centers for Disease Control and Prevention. In fact, her first book, Beating Back the Devil, detailed her experiences with CDC's Epidemic Investigation Service (EIS), the team dispatched anywhere in the world that's experiencing an unusual infectious disease event. From her book's website: I was following a group of disease detectives from the Centers for Disease Control and Prevention, the CDC, through an investigation of bizarre skin infections in Los Angeles. The CDC wanted to know where men were picking them up. I wanted to know something more fundamental: How could a minor problem — something that the victims all described as looking like a tiny spider bite — blow up into massive infections that ate away at skin and muscle, put people into the hospital for weeks and drained their health and their bank accounts? Where had it come from? And if it could do that, what else was it capable of? Maryn's one of the best science writers in the world in terms of mastering her subject and making it widely accessible. Of course, her webinar will be of interest to anyone concerned about the proliferation of drug-resistant infectious diseases and how to design drugs to stay a step ahead of evolution. But she's also a great model to emulate for anyone trying to make their scientific work more approachable to non-experts. You might even learn a thing or two about telling a gripping story. And, thanks to your American Chemical Society, dialing into the webinar is FREE. Go here to register. You don't even need to be an ACS member! You can thank me later. The webinar will be archived but you can also hear from Maryn McKenna on a regular basis at her Wired Science blog, Superbug and on Twitter...

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#ChemCoach Carnival: From Big Pharma to Non-Profit
Oct25

#ChemCoach Carnival: From Big Pharma to Non-Profit

We're almost at the end of National Chemistry week, folks, and the Haystack is finally kicking in to blogger SeeArrOh's now rampant #ChemCoach carnival. The goal of any carnival is to get a lot of different bloggers to post on the same topic--in this case, to write about how they got to where they are today as a way of educating young chemists on their career options. Round-ups of the dozens of posts this week can be found here, here, and here. Since the science writing field has been well covered here and by our own Carmen Drahl, and because the Haystack is focused on all things pharma, I thought I'd enlist the help of someone with a much more illustrious career than my own. Without further ado, I give you some words of career wisdom from TB Alliance's chemistry guru Christopher Cooper: Your current job.   I’m Senior Director of Chemistry at the Global Alliance for TB Drug Development (TB Alliance), a non-profit, product development partnership headquartered in New York City.  My job encompasses all chemistry activities for the Alliance from early-, mid-, and late-stage drug discovery right through drug substance/API manufacturing for clinical trials.  The TB Alliance is dedicated to identifying safe, novel chemical entities for the rapid treatment of tuberculosis worldwide, and my job is to oversee the Alliance’s chemistry needs to achieve our goals (seewww.tballiance.org for more details). What you do in a standard "work day."   Define “standard” … oh, and define “work day,” as well, please? All kidding aside, working for a small (~45 employees), entrepreneurial, research and development organization means that every day is truly different, whether it’s engaged in project team discussions with collaborators in Chicago and Belgium, or proposing new analogues/chemical series to pursue with chemists in Auckland or Seoul!  In fact, as we engage chemists (medicinal, process, manufacturing) on TB Alliance projects around the globe, my work “day” doesn’t really begin or end.  After all, if it’s 9:00 P.M. on the East Coast, it’s already 9:00 A.M. in Beijing!  Fortunately, the virtual nature of our business model translates into my own flexibility in addressing issues wherever and whenever they occur … and I don’t have to wash my glassware anymore (yey!). What kind of schooling / training / experience helped you get there?   In many ways, my background would appear fairly conventional, despite the more unconventional nature of my current position.  I received my B.S. from Clemson University in 1980, and my M.S. (1982) and Ph.D.’s (1988) from Stanford.  Having worked briefly in the pharmaceutical industry (CIBA-Geigy from 1982-1984), I was eager to return so I accepted a position...

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TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay
Apr13

TEDMED: Andrew Read’s Five Tips For Keeping Superbugs At Bay

Researchers may like to think they're pretty smart, but you could argue that bacteria have also got some bragging rights. Every day, microbes develop resistance to even the most powerful antibiotics scientists have developed. Andrew Read thinks evolution is the best lens for staring down the superbugs. He took the stage Thursday at TEDMED, where he warned, "we're picking a fight with natural selection." "Picking a fight without Darwin is like going to the moon without Newton," Read added. "We are in the dark ages when it comes to evolutionary management." Read, director of Penn State University's Center for Infectious Disease Dynamics, sat down with me on Thursday and shared a few principles he thinks the scientific community should keep in mind in order to keep antibiotic resistance in check. Here are his five tips for would-be superbug slayers. Get smart with the drugs you've already got. "We can't rely on a continual supply of new drugs," Read said. Many firms have already exited antibiotic research, he notes. "You can see that the markets aren't good enough right now to drive innovation," since new antibiotics are precious and used only for patients' most severe infections rather than being prescribed widely. Read says firms should continually evaluate dosing and combination strategies with established drugs in order to stave off resistance. "I'm not saying we shouldn't discover new antimicrobials," Read stressed. "In some situations, like malaria, it's really critical. But we don't want to put all our eggs in that basket." Learn from what works. "I think magic bullets are the exception rather than the rule," Read says. But researchers should focus on why wildly successful therapies were so. "Why was that pathogen unable to get around the smallpox vaccine? Why is chloroquine still working against some malarias in some parts of the world when it's has failed miserably in others?" Read asked. Make the right matches for combination therapies. Read notes that some antimalarial drug combinations have consisted of drugs with markedly different half-lives. In effect, once the first drug has left the human body, all that's left is the other drug, a monotherapy. "And that's dangerous," a breeding ground for resistance, Read cautions. "You want to be combining drugs that have similar half-lives." Researchers should also think about whether their antibiotics become more lethal to microbes when used in combination, or less lethal, Read says. Evidence suggests that less lethal is better, he says. According to work from Roy Kishony's lab at Harvard Medical School, if an antibiotic combo is less lethal, once resistance develops to one drug (call it drug A) in the pair, then drug B can...

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Antibacterial Resistance – Learning Bacterial Tricks
Mar23

Antibacterial Resistance – Learning Bacterial Tricks

Virulent bacteria are growing increasingly resilient against our best antibiotics. Each day seems to bring a new story: MRSA outbreaks, resistant salmonella, or tough-to-treat tuberculosis. Just last week, World Health Organization director-general Dr. Margaret Chan delivered an address in Copenhagen, where she cautioned: “We are losing our first-line antimicrobials . . . in terms of replacement antibiotics, the pipeline is virtually dry. The cupboard is nearly bare.” (Click here for The Haystack’s past coverage of the development of new antibacterials). Why have our drugs stopped working? Recent research from St. Jude’s (Science, 2012, 1110) attempted to answer that question. Using X-ray crystallography, a technique used to see structures at the atomic level, the researchers were able to capture a critical moment when a drug binds to DHPS, its bacterial enzyme target. The scientists could then predict how bacteria evolve to dodge further biocidal bullets. The antibacterial medicines caught in the act by the St. Jude’s researchers are the sulfa drugs (see right), former front-line treatments many doctors push to the bottom of treatment regimens, due to increasingly resistant bacterial strains. Researchers knew resistance had something to do with the drugs' mechanism of action; sulfa drugs mimic the binding of PABA – para-aminobenzoic acid, a compound found in many sunscreens (Chemical Note: PABA occurs naturally as bacterial vitamin H1, and can also be found in yeast and plants. Chemists often borrow naturally-occurring compounds for industrial uses; two prominent examples are vanillin and Vitamin C). Disruption of this PABA binding shuts down bacterial DNA replication, stopping reproduction. Before now, however, no one had succeeded in growing crystals of the active site that actually showed the drugs interacting with the enzymatic intermediate. Let’s take one more step back: how does PABA attach itself? The enzyme we’re discussing, DHPS, catalyzes bond formation between PABA and intermediates known as pterins (see picture, left). Earlier researchers believed that this molecular hook-up operated by an SN2 mechanism, a reaction where the PABA kicks out a small piece of the pterin to form a new C-N bond. We chemists would say that SN2 means concerted bond formation, meaning that PABA would bind at the same time as the leaving group (OPPi), well, leaves. Turns out that picture’s not quite right: it's more SN1-like, which means that the pterin first forms a positively-charged, enzyme-stabilized species! As you can imagine, this is no small feat, since the reaction works at physiological pH, in water, which could hydrate the intermediate (but doesn’t). Nope – instead, this charged molecule sits around waiting for a PABA - or a sulfa drug - to bind to it. When PABA binds, the complex exits...

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Exploring Rational Drug Design
Feb17

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! 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 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...

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