Chemical Space Explorers

One startling omission from my Acc. Chem. Res. post? Jean-Louis Reymond's review on the vastness of his generated database GDB-17, a.k.a. The Chemical Space Project. With over 166 billion compounds  Reymond claims to have produced the largest virtual library ever assembled. The best part? It's 99.9% new-to-science compounds. As Derek has quipped, chemical space truly is "Big. Really big."

Trudging along through chemical space, using Dr. Reymond's MQN-browser.
(I realize there's no way some of these are stable - 49? 54? - but they sure do look cool!)

Of these innumerable options, how do we decide what to make next? It's like that old Wall Street saw about how "Buy low, sell high" sounds easy, but takes a lifetime to figure out. It seems straightforward to say that you've generated billions of druglike compounds in silico, but how do you find out which ones are actually drugs?

You have to start somewhere. I still recall the first "chemical space exploration" paper that truly caught my eye - a 2009 J. Med. Chem. scribed by Will Pitt and colleagues at UCB (I still keep a dog-eared copy in my file cabinet). Using machine learning, the team constructed a library (VEHICLe) containing synthetically feasible heterocyclic compounds, most of which had never been made.

Offering a partial update to Will Pitt's "Figure 6" from his 2009 J. Med. Chem. I searched SciFinder for each ring system as a substructure of reaction products, allowing for certain substitutions (say, fused phenyl in place of endocyclic olefin) and considering tautomers. By my count: 10 down, 12 to go!

Pitt issued a challenge in the introduction:

"With this work, we aim to provide fresh stimulus to creative organic chemists by highlighting a small set of apparently simple ring systems that are predicted to be tractable but are, to the best of our knowledge, unconquered."

Heady stuff. So, who will step forward to try these tantalizing targets? Someone certainly should, as Prof. Reymond seems to suggest with his own forward-leaning graphic:

GDB-17 "nearest neighbors" - closely related to known drugs, but not yet synthesized.
(I couldn't find anything similar in SciFinder, either)
Source: J-L Reymond, 2015 Acc. Chem. Res.

Do you suppose an academic candidate could make a convincing case? I'd be tickled pink if something along these lines were sent off to the NIH R01 office:

"Dear [insert funding agency] - Listen, I really want to develop novel molecules to improve human health, but I'm not collecting plants or culturing microbes, and it's too tough to compete with industry head-on. But say, there's this guy who's looked at more compounds than any other human being alive, and he says there's some structures that look really close to existing drugs that nobody's ever tried making. Mind giving me some cash for that?"

Good luck, chemical space explorers. 

The Future is Now

The Graf Zeppelin. Source: Ad Orientem

I’ll admit it: I love to look at antiquated predictions of how the world will be in 50 or 100 years. These glimpses into the future strongly reflect their era; the audience had to grasp the author’s intent and direction using metaphors and extensions of the technology they knew. 


We chuckle at predictions such as world zeppelin travel and automated horse-carriages, much like future generations might wrinkle their noses at our notion of a “world wide web” or “smart phones.”

A new (old!) article, published in the 1901 Ladies’ Home Journal by one John Elfreth Watkins, Jr., puts forth several such predictions (thanks to the Saturday Evening Post and the BBC; see reddit or imgur for the full article). Mr. Watkins apparently spoke with “the wisest and most careful men in our greatest institutions of science and learning” in a quest to determine what “…will have been wrought…before the dawn of 2001.”

All told, Mr. Watkins made 28 predictions in his article, and the BBC article covered 14, the Post 17. Since this is primarily a science blog, I’ll comment on some of the tech highlights; sadly, most of these didn’t make the cut for the preceding articles.

The drug designer's "killer app"

 “Few drugs will be swallowed or taken into the stomach” – Drug designers, aiming always for the killer app of oral availability, would be amused to hear this. The author was correct about a later statement in this section, though: “The living body will to all medical purposes be transparent.” Mr. Watkins waxes about invisible rays allowing physicians to operate on human organs directly, which, with the advent of MRI, PET scans, and endoscopy, is much closer to reality.

“…utensils shall be washed in chemicals fatal to disease microbes” – Antibacterial hand soaps, bleach, and wastewater sanitation systems maintain healthy conditions in large restaurants.

“There will be no C, X, or Q in our every-day alphabet” – Uh-oh, don’t tell any organic chemists! C is, of course, carbon, and X is a placeholder for halogens, a math variable, part of road signs (X-ing), holidays (Xmas), and of course where pirates bury their treasure!

“The soil will be kept enriched by plants which take their nutrition from the air and give fertility to the earth” – Nitrogen fixation, anyone? Legumes such as peas, beans, and carob are often rotated in with other food crops to ensure proper soil nutrients. In 1901, Watkins still had no inkling of the Great War to come, or how the Haber-Bosch process would lead to cheap fertilizers and increased munitions.

Might there be a Schrock-Chirik process in our fixation future?

“Plants will be made proof against disease microbes just as readily as man is to-day against smallpox” – Mr. Watkins refers, of course, to Jenner’s development of the cowpox vaccine for smallpox treatment. In the 21^st Century, industrial conglomerates such as Dow Agro, DuPont Crop Science, BASF, Syngenta, and Monsanto work towards pest-resistant crops and pesticides.

An FDA inspector checks a salad bar. Source: FDA Flickr.
(Did you know the FDA maintains a Flickr account? I didn't!)

 “Storekeepers who expose food to air breathed out by patrons or to the atmosphere of the busy streets will be arrested with those who sell stale or adulterated produce” – The modern FDA, presaged 5 years before its formation in 1906, now inspects both food and drugs from production through sale to consumers.

Pharma Mascots - Cartoon Stand-Ins for Disease

Credit: Time Magazine

While glancing through some magazines yesterday, I came across a troubling ad for Abilify (aripiprazole). It’s not the drug that irks me, but rather the imagery - in the ad, depression takes the form of a sad, hovering blue bathrobe, stalking the nervous patient down the sidewalk.

I get it. Abilify helps a lot of people with severe depression feel normal enough to get outside and live. But the picture carries a menacing subtext: Without this med, depression will cover you and weigh you down, like a thick, fuzzy robe of gloom.

Credit: mucinex.com

This is, of course, nothing new. Marketers make their livings playing on our subconscious reactions to colors, smells, and situations. But pharmaceutical marketing takes the message one step further. Many people recognize the signs and symptoms of disease: sore joints, skin discoloration, cough, fever, blurred vision. But do they know about the underlying condition, or anything about the drugs* used to treat it?

Well, cartoons to the rescue! Nowadays, each med gets its very own mascot, a stand-in for all the aches and pains brought on by the specific problem. For Uloric (febuxostat), a gout flare treatment, a man carries an Erlenmeyer flask full of green liquid meant to represent uric acid (which is actually a white solid). His obviously stunted gait and heaving effort evokes gout’s painful inflammation. Pristiq (desvenlafaxine), an antidepressant marketed by Wyeth before the Pfizer takeover, showed a sad, small wind-up doll, meant to show the effort needed to “get going” when depressed.

Credit: lamisil.com

Lamisil (terbinafine) needed a mascot to represent a fairly common locker room ailment – foot fungus. The myco-avatar? Meet Digger, a small, spiky, yellow critter who represents discomfort and skin discoloration. His long claws are meant to simulate the scratching and burning brought on by infection.

Finally, Mucinex (guaifenisin) gives us Mr. Mucus, a hefty green glob used as a mucus analogy. He is, perhaps, the most over-the-top mascot, in that his only function seems to sit around as chronic congestion might.

Do these disease caricatures actually help someone, say, decide between two alternative treatments? Or appreciate the risks and side effects behind a certain treatment? Or are they just cute graphics to put on T-shirts and coffee mugs?

*In case you’re wondering, I didn’t forget: here’s the structure of the drugs

Update (12/24/11) - Added guaifenisin, generic name for Mucinex. The same generic drug is indeed found in several OTC medications.

Illegal Drugs Spur Chemists to Create Cures

White powders marketed on grocery shelves as “bath salts” are quickly becoming problematic for politicians and police, as reported in the July 17^th New York Times.  These “salts,” derivatives of a compound called methylenedioxypyrovalerone (MDPV) cause many of the same symptoms as methamphetamine intoxication. The wide availability of these new mixtures, compounded by their ease of synthesis and seemingly no lack of supply, has led to an explosion in their abuse (Note: I won’t cover the chemistry behind MDPV, the active ingredient, because my in silico mentor David Kroll’s posts on Terra Sigilata have mostly covered it).

That’s the gist of the article, in which illicit chemical synthesis fuels a new drug craze, and the public perception of chemists is dragged down again by sound bites such as “state bans thwarted by chemists who have to change only one molecule… to make [the salts] legal.” What happened to fair and balanced coverage?

For every illegal manufacturer of psychoactive compounds hoping for addiction to promote sales, there are many more chemists working on analogs of bioactive substances to treat disease.  Compounds that show high potential for abuse tend to interact with three neurotransmitters: serotonin, dopamine, and norepinephrine. In the case of bath salts, the main ingredient is a norepinephrine-dopamine reuptake inhibitor (NDRI), which allows these neurotransmitters to stay longer in the synapse, creating feelings of pleasure and wakefulness. Phenethylamines, such as MDPV, meth, or Ecstasy, the popular club drug, are one major class of compounds which activates these receptors, and are easily tweaked synthetically to prepare drug leads for Parkinson’s disease, schizophrenia, and ADHD.

Prof. David E. Nichols, of Purdue University, has devoted much of his career to understanding the mechanisms by which addictive drugs can interact with brain receptors, and designing novel compounds to take advantage of these traits (See this October 30, 2010 Wall Street Journal piece for Nichols’ comments regarding black market applications of his academic work). Prof. Nichols has synthesized variants of psilocybin, mescaline, and notably for this particular story, MMAI, a “cyclized” version of a typical methamphetamine scaffold.  On the day the NYT article went to press, Prof. Nichols had a J. Med. Chem. ASAP publication (DOI: 10.1021/jm200334c) appear online, in which his group prepared four new methylated analogs of their lead compound dihydrexidine. This analog, developed off the phenethylamine scaffold, has been shown to bind to the D₁ dopamine receptor, and both improve blood flow to the brain and to reverse Parkinson's-like symptoms.



Photo Credit: obrag.org

 Two other medicinal chemists are using methamphetamine derivatives as “Trojan horses” to trick the body into immunizing itself against the drugs. Their end goal is a vaccine that could be administered to control meth addiction. Kim Janda, of the Scripps Research Institute, and F. Ivy Carroll of the Research Triangle Institute (just down the block from David Kroll!) have both recently reported their groups’ respective efforts towards methamphetamine vaccines. Each group strategically introduces a hapten, an immunological “stamp” that latches onto a human protein, which the body can use to recruit white blood cells to the foreign substance.

Janda (JACS 2011, 6587) attaches a six-carbon chain ending in a thiol (SH) group to the amino group of (+)-methamphetamine, the more potent enantiomer, and observes high antibody titres in mouse models. Carroll (J Med Chem, 2011, ASAP) also uses a sulfur antigen, but attaches his via an amide linker connected to the aromatic core. After connecting this linker to a suitable immune-responsive protein, Carroll generates a monoclonal antibody with a 6.8 nm K_D for (+)-meth.

Update (July 30, 6:50PM) - Changed "bloodstream" to "synapse," since commenter gippgig is (again) correct that the compounds influence synaptic function, not bloodstream chemistry. Thanks!