Automatic for the Chemist

For decades, chemists have toiled over reaction flasks searching for new ways to mix and match atoms to make new molecules with which to cure ills, boost crops and generally improve our standard of living. There are countless still who spend their working days scouring the scientific literature for shortcuts and using trial and error to find fast and efficient synthetic routes to that all-powerful catalyst or a wonder drug from an obscure soil fungus. Less than flask-happy chemists hope to use computer programs to design their reactions for them and ultimately control the robot arm to shake the test-tube for them.

German chemist Johann Gasteiger together with colleagues at the Institute for Organic Chemistry at the University of Erlangen-Nurnberg has spent fifteen years or so designing a neural network program that might be a first step on the way to hanging up the lab-coat.

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His system uses the accrued information found in commercial databases containing hundreds of thousands of chemical reactions – each with its own reaction conditions: cooking time, pressure, catalysts, reagents and acidity, listed together with physical parameters about the molecules involved.

Today, a chemist might search such a database manually or use a search program to pick out reactions of interest. This, according to Gasteiger, can get embarrassing, “A single search can lead to a list of several hundred reactions from a database that can contain millions,” he explains, “so manual analysis is both laborious and time consuming.” One way to cut down on the effort involved is to classify the multitude of reactions.

Chemists have been classifying whole swathes of reactions for years by naming them after their inventors – the Wittig, the Beckman, the Diels-Alder, but, posits Gasteiger, this system does not help very much in indicating to the chemist exactly what takes place in a particular reaction brew. This is especially true because there are literally dozens of variants in each class. He felt that the solution would be a neural network could do the sorting for him. “There are two approaches to teaching a neural network chemistry”, explains Gasteiger, “supervised and unsupervised learning.” The former is labour intensive and involves presenting the network with input patterns for thousands of reactions and telling it which ones work in which circumstances. “We prefer the unsupervised approach,” says Gasteiger, “It cuts the workload considerably.”

How to teach a neural network chemistry? Gasteiger and his team have used a Kohonen network – a computer model of how our brains organise sensory information – sights, sounds, and tactile feelings in which inputs are mapped onto a two-dimensional network of neurones. By extending this mapping process to the properties of reactions in a database they could gain important information about many reactions at once.

Instead of sensory inputs for the network the researchers used each factor affecting a reaction – such as temperature and acidity – and these co-ordinates were fed into the neural network.

The team picked on a single broad class of reactions to test their networking ideas: reactions that involved adding a carbon-hydrogen group to an alkene. This type of reaction encompasses a variety of important schemes used to produce many industrially useful chemicals such as esters for artificial flavourings – so-called Michael additions, Friedel-Crafts alkylations by alkenes and free radical additions to alkenes.

They used a search program to narrow things down first – they obtained a set of 120 reactions from a 370 000 strong database. They then chose seven characteristic physical properties associated with the actual portion of the molecule that changes – the reaction centre – as the input for the neural network. For instance, the ability of the double bonds between carbon atoms to attract electrons, its electronegativity, the total charge, and the degree of possible distortion of the electron cloud in the bond, its polarisability.

The network they used is a grid of 12×12 neurones with a “weight” associated with the seven chosen variables. When a reaction is input the variables are mapped into the neurone whose weights are most similar to the input. Reactions are input sequentially and after each entry the weights on each neurone are adjusted to make them more similar to the input variables. The adjustment is highest the closer the hit on each neurone and tails off with distance.

The next input if it has similar variables will be mapped on to a neurone close to the first but if it is different a neurone it will locate on a distant neurone and the weights will be adjusted again. The result of these weight adjustments is that the network is trained to recognise patterns of parameters and to place a particular reaction accordingly. Eventually a 2D landscape of reactions is built up with similar reactions close to each other forming groups of reaction types. Logically, reactions far apart in the landscape are very different. Isolated peaks in the landscape point to unusual and uncommon reactions.

The most exciting aspect of the way Gasteiger’s neural network can classify reactions is not that it verifies the system already used by chemists every day, but that if they have a new compound they can look at the seven variables, feed them into the trained network and the network will assign it to a specific neurone. This allows the chemist to see the likely reaction a molecule will undergo in the lab. For instance, if a molecule finds itself at the centre of the area of the map covered by the so-called Michael addition then it is likely to undergo a standard Michael addition. If it is further afield it will probably undergo something more exotic.

It took less than 20 seconds for Gasteiger’s team to train the network with their sample of 120 reactions on a Sun workstation. So to train it on the full reaction database would take little more than a day or two allowing some time for checking. Gasteiger points out that computer time once the neural network is trained is very short (less than half a second) so making predictions about a particular molecule is very fast.

Classifying reactions is not the whole story though – once you know what type of reaction a molecule will undergo, the next step is to work out how it can be used to build up more complex molecules. Chemists usually picture a target molecule and cut it up into smaller jigsaw pieces that can then be re-assembled in the reaction flask. The difficulty lies not only in knowing where to make the breaks to simplify the reactions needed to put the puzzle back together, but in finding reactions that can make the lugs of each jigsaw piece fit together properly. This might be where Gasteiger’s neural network could help in predicting what would work.

Corey’s own program for automating the process, LHASA (Logic and Heuristics Applied to Synthetic Analysis), is marketed by LHASA UK, a company based at the University of Leeds). According to Nigel Greene of LHASA UK, “LHASA is a knowledge-based expert system not a reaction database.” It uses what he calls transforms to describe a generic chemical reaction class e.g. the Michael addition. These transforms are compiled manually from a study of the chemical literature. The program then searches the query compound for the correct stuctural requirements in order to apply the transforms, which is tantamount to picturing the break-up of the jigsaw.

According to James Hendrickson of Brandeis University, “there are literally millions of different routes possible, from different starting materials, to any substance of interest.” He and his team have devised a program (SYNGEN), which can find the shortest route to any molecule from available starting materials. First, SYNGEN looks for the best way to dismantle the target jigsaw. Then, for each dissection it generates the reactive chemical groups needed to carry out that reaction sequence to build the product. Results are displayed onscreen. “In a number of cases to date, the computer has generated the current industrial routes to several pharmaceuticals, such as estrone,” explains Hendrickson. SYNGEN has also proposed more efficient routes to numerous compounds such as lysergic acid, the precursor to ergot drugs and LSD. A new version of the program is in development ready for licensing to pharmaceutical companies this year.

William Jorgensen of Yale University in New Haven Connecticut is working on yet another program CAMEO (Computer Aided Mechanistic Evaluation of Organic reactions). The chemist feeds the starting materials – using a sketchpad – and the reaction conditions – via drop-down menus – into CAMEO, virtually speaking, and the program attempts to predict the course of the reaction. It assembles a reaction from underlying mechanistic steps because as Jorgensen points out a large fraction of organic reactions are just combinations of various fundamental steps.

Sometimes CAMEO (also marketed by LHASA UK) claims no reaction product will emerge, a chemical rule would be broken if it were. The chemist can then run the reaction again virtually in a different solvent or at a higher temperature and watch the result, cutting testing time in the lab.

The various programs apart may not seem to offer a chance for the chemist to boost their leisure time but together they may provide a way of classifying reaction types, working out what type of reaction might take to yield a new molecule using a neural network, feeding it into CAMEO to see whether reactions with other molecules could lead to it and then using SYNGEN to optimise the route.

Some chemists are not worried about losing their jobs just yet though. Al Meyers of Colorado State University at Fort Collins, says, “There is a delicate balance between reacting species, solvents concentrations, selective reaction behaviour, and most important, the human ability to observe what is happening, cannot be incorporated into a reaction software package.” Software will play its role though, “The synthesis programs can bring into focus the many options available to the seasoned chemist”, he adds.

We will have to wait and see who or what is shaking the reaction flasks in ten years time.

Touch Wood! A Guide to Viagra Louts

Elephant penis, photo by 雷竞技官网
When it comes to keeping up appearances, even a bucketful of gooey oysters, half a dozen XXX videos and a smattering of sensual massage don’t always have the desired result. In desperation, even tiger penis tea and rhino horn – is it hung round the neck, or what? – sound more appealing than the best medicine had to offer those who are willy nilly: a drug to circumvent the problem injected straight into the penis through the front opening in one’s underwear. A romantic interlude before lovemaking I don’t think. More a case of ‘take away the pain Doctor, but leave the swelling’.

Then along came Viagra – which was just swell! A solution, or rather a pill, for that little bedroom engineering problem. Medical science had come good, providing a much-needed boost for flaccid men the world over. With medical approval in hand, pharmaceutical company Pfizer launched their product on to a desperate market shooting to number one almost overnight. Prozac? Who needs it when Viagra gets to the root?

The story began several years ago when scientists found a tiny gas molecule called nitric oxide (NO) acting as a chemical communicator in our cells. Importantly, for sexual health, the release of NO by cells in the penis activates an enzyme called guanylate cyclase. This crucial reaction makes another molecule, cyclic guanosine monophosphate (cGMP). CGMP relaxes penile smooth muscle allows the arteries to expand and so blood rushes in giving an erection.

Horny old goat, photo by 雷竞技官网

Normally, a second enzyme (PDE5 found mainly in the penis) gradually breaks down cGMP so without continued stimulation an erection flops. Pop a Viagra though and this second enzyme is blocked. Even the most flaccid of penis will release some NO with erotic stimulation and once it does there is no PDE5 available to damp it down again and for two-thirds of men erection will ensue – within an hour.

Viagra, aka sildenafil citrate, was originally to be a drug for treating angina and high blood pressure. When patients failed to return spare tablets after the clinical trial, though, Pfizer suspected something was up. It turned out that one side-effect was a spontaneous and sustained erection. Pfizer grasped the potential in treating what the doctor will call erectile dysfunction – ‘not getting it up’, to you and me. After the usual safety checks, they carried out a trial on more than 3000 patients aged 19 to 87 to see what effect the drug would have on impotent men and whether it could help them achieve a satisfactory sexual result. Rather than use video cameras to monitor ‘activity’, Pfizer opted for a questionnaire approach and trusted the patients, to be honest.

The responses tallied with anecdotal evidence from the heart patients: Viagra gets it up regardless of problem, general health, race, or age. The amazing thing is that Viagra gets it up in four out of five men regardless of why they are limp. There are so many causes of impotence, from psychological and old-age to injury and prostate problems, that a drug aimed at curing any one problem may not have been so successful. Viagra, or to give it its proper chemical name 1-{[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl}-4-methylpiperazine citrate (here is the pdb file), is satisfaction almost guaranteed despite the name being more of a mouthful than the tiny sky-blue diamond tablets.

Viagra has been available in the USA on prescription since March 1998 and, according to George Dunea of the Cook County Hospital in Chicago writing in the British Medical Journal that year, has probably led to a lot of doctors there with writer’s cramp pumping out almost two million prescriptions! Shares in Pfizer quickly reached a high plateau and should be sustained with anticipated billion dollar sales for next year – sex truly does sell.

Everything in the bedroom is not rosy though – far from it. One bizarre side-effect experienced by some users is a strange blue-green hue to their vision. The colour blindness passes but aside from jokes about too many erections making you blind, some eye specialists are worried about long-term effects on sight. Viagra has also been blamed for headaches, hot flushes, rash, dizziness, diarrhoea, priapism (sustaining an erection for hours after orgasm) and Pfizer provide an even longer list in the accompanying notes.

There is also the tragedy of sixteen men who have died while allegedly using the drug. Eight others died during the clinical trials. There is concern that simply resurrecting your sex life with a drug could have been the cause, with hearts pumping blood to places it has not been for a while. Most victims were in their sixties and seventies, and most had heart problems or diabetes. Although this does not prove that Viagra may have side-effects on the heart – Pfizer’s clinical research found that reduced blood pressure could occur.

Another problem has reared its ugly head too. It did not take long for people to realise that if Viagra can boost the ego, so to speak, of impotent men, then it could probably double the efforts for those without problems. Healthy men claiming impotency may be among the biggest beneficiaries of those millions of prescriptions. Popping a Viagra in the hope of giving even an active sex life that extra rise.

Not surprisingly, an Internet blackmarket quickly emerged with genuine Viagra as well as dubious products called Veagra and Viagre being marketed. Viagra is fast becoming a recreational drug and the UK’s Medicines Control Agency has even set up The Special Enquiry Unit of ‘V-men’ to hunt down anyone illegally selling Viagra. Once Viagra is made available on the NHS later this year, the government has said that individual GPs will be responsible for making sure only needy patients are prescribed it and they will be responsible for the outcome. There have already been more than a dozen attempts to market Viagra illicitly in Britain.

With abuse of drugs come increased risks, especially for particular users. Certain social groups have known for many years that a group of compounds known as organic nitrates (amyl nitrate/nitrite, or poppers, are probably the best known) can speed your pulse, boost libido and allegedly make sex a more fast-paced and thrilling experience. While there are numerous nitrate-based prescription drugs too for treating hypotension including some based on nitroglycerine – the opposite of high blood pressure. The problem is that anyone taking these drugs with Viagra could suffer plummeting blood pressure and possibly death. There have been reports of patients taking nitroglycerine treatment for low blood pressure who have experienced blackouts but doctors are warned to check for other medications and drugs before prescribing Viagra.

But what about the ladies? Pfizer is currently carrying out trials in Europe and discussions are taking place in the US to see whether women with sexual dysfunction, reduced libido, or lubrication problems (which can start at menopause) might benefit from taking the drug. There is now evidence that male erectile dysfunction might be more closely related to similar problems in women where blood flow to the genitals is just as important in sex. What’s sauce for the goose…after all.

There could soon be an alternative to Viagra. Vasomax (phentolamine) made by Zonagen is still passing through the approval pipeline. It apparently has the distinct advantage over Viagra in having only a 20 minute pre-love period. It’s also safer for patients taking nitrates. Pfizer, of course, intend to pre-empt approval of Vasomax and are working on a wafer form of Viagra that would be absorbed through the tongue and so act much more quickly.

The Public Health Minister Tessa Jowell has announced that Viagra will be available by prescription this year, but declined to say how the prescriptions would be limited and exactly how patients would be assessed for need.

Anyone, thinking about Viagra must weigh up the risks. The best bet might be to give the soft lights, romantic music and oysters another try. If you do opt for Viagra just pray you don’t discover you suffer from premature ejaculation…

Article by 雷竞技官网

Science Writer originally appeared in the BBC Tomorrow’s World magazine.

Footnote added subsequently: But, what about the question of dissolving it in water? Sildenafil citrate is orally available, so presumably it dissolves in water but I doubt the manufacturers will be creating a fizzy version any day soon.

Since this article was first published several other drugs have come available – Cialis, Levitra, Uprima (goes under the tongue, sub lingually as it were), and new delivery methods for Alprostadil.

More on Erectile Dysfunction and Premature Ejaculation, Men’s Health News

Interview with Eric Scerri

Interview with Eric Scerri from The Alchemist archive 1998-04-03

Eric Scerri

Professor Eric Scerri, born 30th August 1953, Malta. Nominated for the Dexter Award in the History of Chemistry. Interested in the philosophy of chemistry, especially philosophical aspects of the periodic system and of quantum chemistry.

Assistant Professor, Bradley University, Illinois.

Major life events:
Gaining a PhD in History and Philosophy of Science at King’s College, London on the Relationship of Chemistry to Quantum Mechanics. Being invited to the home of philosopher of science Sir Karl Popper for a discussion on quantum mechanics, chemistry, philosophy, life and the universe. Going to the US as a postdoctoral fellow in History and Philosophy of Science at Caltech. Becoming editor of Foundations of Chemistry.

How did you get your current job?
Job advert in Chemical and Engineering News.

What do you enjoy about your work?
Lecturing to students and generally interacting with people. Being paid to do what I enjoy the most, chemistry.

What do you hate about your industry?
The presence of large numbers of people who do no research, do not keep up with recent developments and pontificate endlessly about how “professional” they are.

What was your first experiment?
My first experiment while teaching was the fountain experiment.

Did it work?
No it did not. As anyone who has tried it will tell you, it’s tricky. I made sure I got it to work the second time.

What was your chemistry teacher at school like?
Excellent, warm and inspiring. Both women: Mrs Davis and Mrs Walden at Walpole Grammar, Ealing, London. The school has now been demolished to make space for a housing estate.

Meeting Popper must have been a formative experience?
You bet! First, he got very angry with me because I had sent him an article in which I was criticising his views on the discovery of hafnium. According to him and many others Bohr predicted that hafnium should be a transition metal and not a rare earth and that led directly to the discovery of hafnium by Coster and von Hevesey. The full story is far more complicated as I and others have emphasised.

Popper in fact accepted my specific criticisms on the hafnium case. I think his initial anger was a sort of knee-jerk reaction, which he had to all critics. After about five minutes, he became a perfectly charming host and answered all my questions and made me feel like an equal even in purely philosophical matters.

What is your greatest strength?
Presentation of ideas in lectures. Being able to criticise arguments.

Sometimes over-critical.

What advice would you give a younger scientist?
Concentrate on mastering mathematical techniques. If the student ever wants to go into theory she will have to be a master of mathematical techniques. Chemical theory is very, very interesting.

What would you rather be if not a scientist?
A Jazz and Blues 雷竞技官网 ian.

In whose band?
In my own band! I have been playing since I was 16 or so.

Which scientist from history would you like to meet?
Linus Pauling

What would you ask him?
About the genesis of quantum chemistry and about the people he came into contact with during his postdoctoral stay in Germany. I think he had the deepest respect for them but was personally more interested in applications to chemistry than reaching a deep understanding of quantum physics. His own approach may have appeared a little too cavalier to the European purists. By his own admission Pauling was working with Bohr’s old quantum theory when he first went to Europe only to be informed by Wolfgang Pauli that more sophisticated versions of quantum mechanics had been developed. Pauling immediately made the switch.

How has the Internet influenced what you do?
Enormously. First of all on a practical level I can find addresses, e-mails, phone numbers of anyone I care to with a little bit of searching. If I read an interesting article I can track down the author and ask them a question a few moments after first reading their ideas.

I should also point out that the Internet brings problems. A student recently wrote a paper for me on the history of the periodic table. He referred exclusively to material on the Internet. Most of the paper was filled with inaccuracies, complete mistakes etc. It was not the student’s fault. The problem is that anyone can set up a beautifully illustrated web page without bothering about the academic content and cast it out on to the Web for unsuspecting students to find. There is of course no [peer] review process for what goes on to the Web.

Wasn’t the student a bit naive to assume total credibility of unqualified sources?
Okay, you are right. He was not a brilliant student and he was lazy. Let’s just say it is tempting for students to sit in their own rooms and surf the Web instead of getting their butts into the library.

Why do you think the public fears science?
Lack of knowledge of course and the hard-edged and clinical image portrayed by many scientists.

What are the ultimate goals for chemists?
I am a philosopher of chemistry and chemical educator. I cannot really answer this question which seems to be directed towards “real chemists”. But do you really mean “ultimate goals”? If I were a theoretical chemist I would say to be able to calculate everything from first principles so that we would never need to do experiments and could pack up and go home. If I were a real chemist reaching such “ultimate goals” would not be much fun.

What will chemistry do in the next ten years?
Nor am I a fortune-teller.

You could speculate though…
Well, I really think computational chemistry and modelling will go on expanding as quickly as do developments in the computer industry. Chemists are going to have to get used to the idea that more and more “experiments” will be done on the computer. This should not imply however that quantum chemistry could explain everything in chemistry – that chemistry has been reduced. Far from it. It just means that computational chemistry can be used as a useful tool along with the various spectroscopic techniques, which have already revolutionised chemistry.

What invention would you like to wipe from history?
Chemical weaponry