Ich kann Deine Fragen gut nachvollziehen, weil sie völlig berechtigt sind.
Auch in anderen Foren wir darüber diskutiert. Als "Aussenstehende" ist es für uns aber schwierig nachzuvollziehen, was da im Labor wirklich passiert und leider scheint es so zu sein, dass dort nicht alles so ultraoptimal läuft wie vielleicht bei anderen Projekten. Forschung wird heute immer mit Hochdruck vorangetrieben, ob die Ergebnisse dadurch besser werden, steht auf einem anderen Blatt.
Anworten darauf findest Du z.B. im Rothberg-Forum. Dort schreibt
Wolfgang Hinz vom Rothberg Institute:
Here are some answers to the questions posted:
1. Is there ANY progress in laboratory tests now? How many molecules have shown predicted activity? What is the number of false-positives results?
To date we do not have significant success of candidates tested in our cell based screens. The reason for this is probably based in the type of assay we are running on the compounds themselves. Whereas computational screening is limited to specific protein targets, our screen test the candidates ability to affect the growth of the cell. The cells are complicated systems which has the targets integrated in interwoven pathways which we known are at the root of Tuberous Sclerosis. The test determines if the compounds generally affect the growth of the cells or even induces cell death for diseased cell lines (cell lines which lack the one of the two functional TSC genes).
In our laboratory assays we do not measure the binding of candidates to individual targets (called biochemical screening) but the technology we use has been shown to be able to distinguish between strong and weak binders. Your obvious question is why don't the predicted strong binders of our targets work in cells? The answer to this has caused many medicinal chemists and researchers around the world headaches for generations. One possible answer is: the binding of the target is not achieving the desired biological effect, i.e. is not affecting the activity of the target or the effect is irrelevant to the growth/death of the cell. Another possible answer is that the cell is bypassing the effect by using alternative pathways to transmit the signal (we are trying to influence the signaling pathways in which the TSC genes play a role). Your obvious next question is: What are you going to do about this? The answer: We will search for new targets and possibly develop some biochemical screens to probe the disease mechanism.
2. What is redundancy of the project? Have you got any plans to publish it? Can you determine it?
We are planning to reduce the redundancy of our calculations significantly. We also intend to publish on the overall design of D2OL and what we have learned from this project in peer reviewed journals. The redundancy is determined from various numbers available to us. The aim is to increase throughput by reducing redundancy.
3. Why the D2OL was selected in spite of the fact that pharmacophore-based methods are much faster and provide much accurate result? (if we compare some pharmacophore-based programs and D2OL, we can see that D2OL is more than 10000 times slower).
Pharmacophore-based methods are of great value if indeed appropriate information is available. Pharmacophore-based methods are knowledge-based, i.e. they require significant binding studies of multiple mediocre binders in order to develop pharmacophore models accurate enough for the prediction of binding of unknowns. Flexible ligand based docking only requires a good crystal structure of the target in order to produce similar results. We have little or no binding information of ligands available for generating pharmacophore-based models.
4. Have you got any links to published SMILES, Molfile or SDfile files that contain the results of our work?
We are hoping to publish on the development of the system and on some results obtained in the near future. These publications will contain the exact results produced by users which were used to obtain results in the laboratory.
Desweiteren meint Charles Beckius, der Administrator:
In mid October, we held our Courage Fund Award Conference for scientific collaboration. I am behind in updating the web page, but there was a definite atmosphere of progress with intriguing directions from all parties. I will need to check what information is presentable here or on the web, as I can not pre-empt publication.
Was Du natürlich auch machen könntest: schreib "Dr. Bonnie", gemeint ist Bonnie E. Gould Rothberg, MD und frag ihn konkret, wie es um das Projekt steht. Das einfachste dürfte aber sein: ein Posting im Rothberg-Forum (
http://www.childhooddiseases.org/cgi-tsc/ultimatebb.cgi
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