þÿ

By indexing these compounds in relevant search engines (I am working
with

to make this happen) as UsefulChem molecules

available upon request (and justification) we have an opportunity to
close the loop on a practical Open Science project.

By the loop I mean a complete iteration from hypothesis to deciding
which compounds to make to actually making them and getting testing
results. These results will confirm or force a modification of the
hypothesis and the cycle goes through another iteration hopefully closer
to producing a useful outcome (a good drug lead compound for
example).

Nature Precedings : doi:10.1038/npre.2007.104.1 : Posted 19 Jun 2007

I imagine that this loop operates in a lot of research groups. But doing
the work under Open Science conditions lets it evolve in new ways.
First of all, the direction of progress is determined by the
collaborators that elect to participate in the process, not
necessarily scientific objectives.

An example of that is our recent shift from the testing of our
compounds as anti-malarial agents to testing them as tumor
inhibitors simply because

Dan Zaharevitz

from the National Cancer Institute

contacted me and suggested that

we submit our compounds.

Nature Precedings : doi:10.1038/npre.2007.104.1 : Posted 19 Jun 2007

Right after we started to submit our compounds, Dan left this

message

The folks at Indiana have done a lot of cool stuff that is well worth looking

. One

thing they have running in a preliminary form is a service that

predicts acompound's activity

in cell lines in the screen. This compound is

predicted to be inactive in the cell lines in the prediction. I actually don't think
that is a bad result. We probably should put up a place to discuss screens and
screening strategy, but essentially a prediction tools such as this summarizes
what is known. A compound that is predicted to be inactive, but turns out to be
active is much more likely to show you something new and interesting than a
compound that is predicted to be active and is active.

So that's the last piece that closes the loop. This web service will make a
prediction about activity of the compounds generated by the CombiUgi algorithm
and rank them. The flagged compounds will be identifed and synthesized then
tested via

NCI's assays for tumor cell inhibition

Nature Precedings : doi:10.1038/npre.2007.104.1 : Posted 19 Jun 2007

My group' s core expertise is the synthetic component. As far as we are
concerned the other 2 processes are black boxes. And for scientists involved
in the computation and testing, our synthesis operation is probably a black
box. But doing everything in the open, hopefully this will allow other
researchers to propose other models and create derivative loops of their own.

We'd love to do the same for the anti-malarial assays but we have not found
an established system in place like NCI that will do substrate screening
routinely at no cost (except shipping of course).

Is it becoming clearer why I think the scientific process can be
automated in novel and useful ways with the progressive adoption of
Open Science?

Nature Precedings : doi:10.1038/npre.2007.104.1 : Posted 19 Jun 2007

C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.OCC%91.Cc1cc(ccc1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCC%91.Cc1cc(ccc1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCC%91.Cc1cc(ccc1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCCC%91.Cc1cc(ccc1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.CSCCC(NC(=O)OC(C)(C)C)%90.CCCCCCCC%91.Cc1cc(ccc1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCCCCC%91.Oc1ccccc1%92.c%931ccc2ccccc2c1
C(=O)%90N%91C%92C(=O)N%93.Oc1ccc(CC(NC(=O)OC(C)(C)C)%90)cc1.CCCCCCCC%91.Cc1cccc(c1O)%92.c%931ccc2ccccc2c1

I find it very interesting that all the top hits involve 2-naphthyl
isocyanide and over half involve boc-methionine. Is this real or even
meaningful? We've been discussing these issues privately and I hope
that Dan, Rajarshi and others continue the discussion openly.

Top 21 Hits (SMILES format) for predicted anti-tumor activity

Nature Precedings : doi:10.1038/npre.2007.104.1 : Posted 19 Jun 2007

The point of this excercise is not so much to prove that this model is correct or
that we have found a new anti-tumor lead (though that would be nice) but that
we can close the scientific loop of hypothesis-synthesis-assay in a completely
open and collaborative scientific environment.

I welcome suggestions of other compounds from our virtual library that might
be worth making (for any disease-related target), as long as we have assays
that someone can run.

We are also working with Tony Williams to see if

ChemSpider

can serve as a

database to store and manage the virtual library, the predicted properties and
the assay results. Hopefully then we could increase the library to several
million molecules.

Nature Precedings : doi:10.1038/npre.2007.104.1 : Posted 19 Jun 2007