Making More Drugs...continued

Size matters

If making libraries is so easy, perhaps this is a case of the bigger the better. The first hitch in that argument comes with planning how to make the library, which involves optimizing a prototype of each class of chemical reaction. With the IRORI system Czarnik says: "Once the route to make a library exists, we anticipate that 10,000 compounds will take about two months with one to two people. But developing the route can take six months."

After chemicals are made they must be tested, to see if they jam the protein they are meant to jam. Testing also takes time and money.

"I think a lot of people are sitting back and wondering if making millions and millions of compounds is really worth it," says Vince Anido, CEO of CombiChem, Inc. (San Diego, Calif.). "The cost is enormous."

"There is as much range of opinion [on library size] as there are people," says Czarnik. "There are devout believers in spending as much time thinking about what you should make as possible, and then never making more than a few hundred compounds. Then there are those who say ‘I would like to know exactly what to make, but I would also like to know the face of God, so perhaps we should make lots of compounds’."

One way of whittling down library size is to bring in the practitioners of rational drug design -- scientists who use the shape (or structure) of the target to deduce which one chemical key will fit the protein lock. The reality is often not so simple.

"The idea of rational drug design is that based on a structure you can predict one perfect drug," says Zuckermann. "That isn’t possible now, and that day may never come. But [rational drug design] can certainly spit out a family of 10,000 compounds that it would be good to make." The computer modeling indicates the rough shape for the key, and custom programs generate a list of chemicals that might fit that description.

Smaller libraries are also more suited to the later stages of drug discovery. The first chemical that shows promise in drug testing rarely ends up being the final drug. Instead there is a period of optimization, in which hundreds of variants of the original ‘lead’ chemical are made and tested. Combinatorial chemistry can be used to make more variants more rapidly. Usually one or more of the variants is an improvement on the original lead chemical.

For combinatorial chemists who still yearn for beefy libraries, the holy grail is a library that contains a lead for every possible protein target. The first step in reaching that holy grail is to minimize duplication, by making the library as structurally diverse as possible. "You can make sure you get diversity of shape, size, and hydrophobicity," says Zuckermann. "Software for that is advanced pretty far, and we have a group at Chiron that does that. It’s useful for avoiding structural similarity. But trying to find parameters that are really meaningful experimentally is very difficult." In the vast universe of chemical shapes, how can you ever define similarity?

CombiChem’s Anido has responded to this dilemma by making everything, at least in a computer. CombiChem researchers have programmed their computers with every chemical building block they can come up with, and the known laws of chemical reactions, and let the computer come up with it’s own trillion-member chemical library. "It’s like taking the alphabet and software that encodes the rules of English," says Anido. "Using those rules, you make all possible words."

Anido initially does a standard screen for lead chemicals, however poor, in a diverse 10,000-member library. Computers tell him what common hole, protrusion, or corner in all these chemicals might have made them all stick to the same target protein. The computer then searches the trillion-member library for other chemicals with that common shape. Anido’s team makes these new chemicals, and the whole process is repeated. Four to six repetitions, each taking approximately three months, usually yields a chemical that is good enough to hand over to a large pharmaceutical company for animal and human testing.

And that is where things slow down. "Combinatorial chemistry has sped up lead discovery dramatically -- finding an active molecule in an assay," says Zuckermann. "But to get a drug on the market you need to do toxicology, animal and human testing, and these take just as long."

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