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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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January 9, 2012

A Look Into the Future?

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Posted by Derek

For a look into a possible drug-discovery future (from the computational optimist viewpoint), you might want to check out a brief bit of science fiction, "Alpha Shock", in the Journal of Computer-Aided Molecular Design. Some excerpts to give you the general idea:

". . .Of course, the compounds were of little value if they couldn’t be formulated. Sanjay was pressed for time, and nanobot development still took several weeks, so he had to go “old school.” Sanjay accessed World Crystallography Repository’s (WCR) formulation suite and entered the 2D structures of his compounds. The system linked to the Amazon Hyper-Cloud and initiated a series of quantum chemical calculations to develop a custom force field for the solid phase simulations. Unfortunately the preliminary results were disappointing, even after more than 100 million combinations of excipients, particle sizes, focusing tails, and polymorphs had been analyzed in detail. He would run a more complete search overnight, but the chances were that the 10-min simulation was telling him what he needed to know: don’t expect these exact compounds to be quite right. . .

. . .“In fact,” Dmitri continued, “I think the best tactic is to turn down the interaction of this transcription factor”—a protein popped out of one node on the map—“with that protein”—another protein materialized—“and this stretch of DNA.” A 3D model of the complex assembled in front of him, slowly rotating, with the most likely binding sites and points of intervention highlighted. “Of course, you only want to disrupt this interaction in the hippocampus, and only when D7 receptor functioning is high.” The relevant pathway maps showed the effects of the blockage on downstream signaling. “Oh, and naturally you also want to turn down oxphos in the mitochondria. So we need either a single molecule that can do both things, or a two-drug combo.”

The overall impression is a bit like Charles Stross, in its deliberate you-haven't-extrapolated-wildly-enough approach. But Stross doesn't put in as many computational chemistry inside jokes, which is probably better for his sales. My first impulse is the same one I have to, say, Ray Kurzweil, that all this stuff may (in fact probably is) on its way, but not by the dates stated. That position allows me to take flak from both sides, which must be some sort of feature that I value.

Comments (16) + TrackBacks (0) | Category: In Silico


1. Henry's cat on January 9, 2012 9:47 AM writes...

Phew. I'll have retired by 2037.

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2. PharmaHeretic on January 9, 2012 10:29 AM writes...

If only it was so easy.. Does any sane person seriously believe such simplistic bullshit?

It appears that they don't understand, or are ignoring, the reality that drug molecules are like software patches in that a perfect solution for a minor problem in one module can screw up something far bigger somewhere else in a way you could not have predicted.

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3. John Wayne on January 9, 2012 10:51 AM writes...

The whole story seems pretty realistic; at the end of the day the chemist gets screwed.

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4. Biotechtranslated on January 9, 2012 11:07 AM writes...

It's obviously science fiction because in the future you won't have a D7 receptor, you would have a D4B(2)(alpha) receptor.


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5. RB Woodweird on January 9, 2012 11:38 AM writes...

"Don't go!" She screamed. He looked back in shock, stopping halfway up the gangplank. The tall, grim-faced MBAians poked at him, urging him to continue up into the ship. "To Serve Chemists..." she cried as they blocked her path, "It's a cookbook!"

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6. Anonymous Academic on January 9, 2012 2:54 PM writes...

For us connoisseurs of techno-optimist hand-waving, can anyone point to equivalent predictions circa 1987? I'm curious how far off base those turned out to be - surely someone claimed that we'd solve the protein-folding problem and make crystallography obsolete by now. (Actually, they're still doing that.)

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7. newnickname on January 9, 2012 2:54 PM writes...

@Derek: Is Murcko still at Vertex? ... I mean the real Murcko, not some computerized, roboticized or 'brain in a jar' simulation of Murcko.

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8. NatProd Nut on January 9, 2012 3:13 PM writes...

7: He is not. He left about a month ago and as far as I know is now an independent consultant.

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9. Chimp Chem on January 9, 2012 3:18 PM writes...


I laughed until I stopped.

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10. SteveM on January 9, 2012 4:25 PM writes...

Meh... I couldn't suspend disbelief - the future setting isn't China.

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11. Pete on January 9, 2012 6:12 PM writes...

I was waiting for Dmitri's (presumably female, given reference to lithe form) anonymous companion to say, "Hey Dimi, You really need to be able measure free intracellular concentration of drug if you want to get this to happen non-virtually..."

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12. Meth lab consultant on January 9, 2012 10:05 PM writes...

Nanobots become the new R&D contractors...WuXi layoff hundreds of human staff.

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13. C on January 9, 2012 10:13 PM writes...

We don't even have this level of biological understanding of E coli growing in a shake flask. How can we ever simulate the human brain?

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14. MolecularGeek on January 10, 2012 1:26 AM writes...

Well, Pfizer is already buying into this vision of the lone modeler telling an army of outsourced chemists what needs to be made.

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15. Anonymous on January 10, 2012 3:12 PM writes...

What I find interesting is that, in the story, they can correctly model the human brain, but they still can't positively predict the weather.

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16. drug_hunter on January 10, 2012 9:07 PM writes...

#15 (anonymous) and #5 (RB) are now tied for "best laugh-out-loud one-liners."

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