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Biotech / Medical : ArQule -- Ignore unavailable to you. Want to Upgrade?

To: ahhaha who wrote (186)	2/9/1998 1:54:00 PM
From: Dr. Voodoo	Respond to of 399

You've missed the point entirely, Why would a cancer cure be found in tree bark? There is absolutely no reason why, it's just found there. Why use it for treating cancer? Because somebody tested it. Penicillin--another accident that has saved millions of lives. Why is it found in mold? It's just there. At the time they found it did they know why it killed bugs? NO At the time they found Taxol did they know why it killed cancerous cells? NO. Now, regarding combinatorial chemistry and the basics of drug discovery. What you seem to be missing are some of the basic assumptions regarding structure space that people are into looking at, basic understandings of numbers of molecules that people are looking at, and a remedial understanding of what is known about molecular recognition and molecular dynamics. For instance, Yes there are N^N possibilities of space to look at. But most people keep the size of the molecules to a minimum--ideally less that MW 500, usually no greater than 1000. So the search of space is somewhat defined even if you are looking for random molecules. Also, often, much is known about the characteristics of the target you are trying to attack, regarding electrostatics, hydrophobicity, active site etc.... So much can be determined a priori of ever making a library if so desired. Much of this is based on the principals of rational drug design that folks like Agouron have used to make protease inhibitors. To assume that we know nothing about the characteristics of molecular recoginition and biologically relavant functionality is a demonstration of profound ignorance. The second point that you have failed to accept is even though there are an infinite combination of electrostatics and molecular shapes and sizes for the molecules you make, there are also an infinite number of shapes and sizes and electrostatic configurations to the biological world we live in. Case in point: Penicillins kill bugs, but the molds that makes penicillins make lots of stuff. Some of it kills the host. Some of it kills the attackers. Some of it is useless and some of it is penicillins. In the case of combinatorial libraries, these molecules, once made are here to stay, and are screened for a variety of biological activities. A third point that you have failed to recognize is the simple fact that Taxol is an inherently difficult molecule to synthesize in the laboratory. Overall yield for a laboratory synthesis of taxol might be only a few percent. Yes we can get all we need from nature and this is a wonderful thing, but someone has to identify the useful substance, isolate it in pure form and characterize it. In addition, in order to go down a relevant pathway to find the best taxoid, YEARS of work may be involved. A fourth point that you have failed to realize is that much of the reasons for the development of combinatorial chemistry has come from the fact that natural products screening has produced very little new products in recent years, and you have to go looking in tree bark in South America to find it. A fifth reason that you have completely neglected to understand is that man made molecules are inherently different than those that mother nature has come up with. It is true that mother nature is the most awesome chemist and biologist on the planet, but mother nature can't do a palladium catalyzed cross coupling the way I can. Why is this important? I can make compounds like AZT and quinolone antibiotics that can be discovered by luck of the draw(check these out if you want) that are useful in treating disease. And furthermore, if I discover these compounds, and they were not synthesized via some biomimetic process that makes a compound resembling a known pharmacophore, then I will have a much better chance of not encountering things like resistance! This is not to say that mother nature hasn't thought of them already. A sixth reason you have discounted entirely is the whole notion that a chemical manipulation of a given pharmacophore into a new one is either all or nothing. Nothing could be further from the truth. Years of work goes into refining structures of biologically active molecules so that you can eat them and they don't decompose(penicillins for instance), so that you do not have the inherent toxicities of the discovered product, so that the rate of absorption is in time with the need for drug... on and on.. Seven, evaluating candidates is in fact hardly daunting, it is just necessary. Once a good lead compound is discovered, high throughput screens are able to evaluate leads quite quickly depending on the stringency of the activity you wish to find and the creativity of the biologist to come up with ways to screen them. And the more molecules that are made from that particular library of related molecules, the more that is known about directions to go in order make a better molecule. The drugs that come out of combinatorial chemistry have strong likelihood to be more specific, potent, and less toxic, just by virtue of productivity. Combinatorial chemistry and high throughput screening gives scientists collectively the ability to make known identifiable compounds and screen BILLIONS of them annually. If you compare this with all of the compounds made in laboratories before the advent of combinatorial chemistry, you will quickly learn that the molecules that we have discovered in nature, in addition to the molecules that have been made in the laboratory constitute only a very small fraction of what will soon be synthesized and screened. The sheer odds of discovery are WAY in favor of combinatorial chemistry. So it boils down to the fact that the machine is worth something. Like a typewriter is better than handwriting, the machine accelerates our output. It doesn't improve it. And the worth something isn't 240x. Science and productivity=infinite compounds in infinite biological screens=infinitely better drugs. Infinite compounds to sell=buyers with infinite screens and infinite money! And to think all these years of modern science, just so nice folks like you can find better time to play golf! Perhaps we should all sit in a hole somewhere and just let you doc's prescribe placebos!