🚀 go-pugleaf

..well the theory is definitely plausible....this is already happening in a
way.  Combinatorial chemistry is a relatively new field which relies on the
analysis of numerous permutations and combinations of proteins and their
response to a substrate
....this requires a lot of computer power...at the moment this type of
experiment or screening process also requires the experiment to be
physically carried out rather than virtually...however it is certainly
conceivable that this process could be carried out entirely in the virtual
sense once we have a better understanding of how proteins etc. function in 3
space.
....I think your oral surgeon is jumping the gun though....the number of
parameters required for an analysis such as the one you suggested would be
astronomical....and unless we engineer some sort of artificial intelligence
in to the computer, these parameters would have to be entered by lowly
humans....
....computer power won't be the answer to the problem of finding vaccines
etc.. but it will certainly speed the process up....remember you first need
the understanding of how the viral proteins and/or genome function during
infection...this requires basic, "traditional" research methods which could
take a lot of time; second you need an understanding of how the gene
products function in 3 space....something which also requires time



Bruce Compton <bcompton@quik.com> wrote in message
news:3834BD00.3EED7723@quik.com...
| Perhaps someone in the medical community  can enlighten me as to the
| outlook for (futuristic?) procedures in the development of vaccines
| through the use of computers.
| My oral surgeon recently suggested that supercomputers in the next
| century would be able to analyze viruses and routinely run through every
|
| chemical combination which could be usd to combat the virus until the
| correct combination is found and a vaccine would be created. He
| suggested that, although perhaps not in our lifetimes, but maybe our
| childrens', any new virus which would appear would be routinely
| eliminated by computer-generated vaccines. Part of the problem, he
| suggested, is developing fast enough computers to run through all the
| combinations. His description reminded me of Microsoft's anti-virus crew
|
| working day and night for a couple of days sometimes to produce a patch
| when e.g. a significant new internet-related virus would be introduced.
| What do you
| think of his theory? Do you think that disease of any kind will be wiped
|
| out by computers by the end of the next century?
|    Any comments or response related to this subject would be immensely
| appreciated.
| Bruce Compton
| bcompton@quik.com
|

I agree with Tyson. Computer are more and more helpful. but we are still not
able to calculate reliably the 3D structure of a single protein. Thus,
saying that one day we will be able to calculate a vaccine with a
supercomputer is science fiction. May be we will. May be not. Notice also
that it is a reductionist/determinist dream that might be totally irrelevant
to biology. For example, will the same supercomputer be able to calculate
the future evolution of man ?

Tyson <tyson@canada.com> wrote:
UIeZ3.72493$it.1740424@news2.rdc1.on.home.com...
> ..well the theory is definitely plausible....this is already happening in
a
> way.  Combinatorial chemistry is a relatively new field which relies on
the
> analysis of numerous permutations and combinations of proteins and their
> response to a substrate
> ....this requires a lot of computer power...at the moment this type of
> experiment or screening process also requires the experiment to be
> physically carried out rather than virtually...however it is certainly
> conceivable that this process could be carried out entirely in the virtual
> sense once we have a better understanding of how proteins etc. function in
3
> space.
> ....I think your oral surgeon is jumping the gun though....the number of
> parameters required for an analysis such as the one you suggested would be
> astronomical....and unless we engineer some sort of artificial
intelligence
> in to the computer, these parameters would have to be entered by lowly
> humans....
> ....computer power won't be the answer to the problem of finding vaccines
> etc.. but it will certainly speed the process up....remember you first
need
> the understanding of how the viral proteins and/or genome function during
> infection...this requires basic, "traditional" research methods which
could
> take a lot of time; second you need an understanding of how the gene
> products function in 3 space....something which also requires time
>
>
>
> Bruce Compton <bcompton@quik.com> wrote in message
> news:3834BD00.3EED7723@quik.com...
> | Perhaps someone in the medical community  can enlighten me as to the
> | outlook for (futuristic?) procedures in the development of vaccines
> | through the use of computers.
> | My oral surgeon recently suggested that supercomputers in the next
> | century would be able to analyze viruses and routinely run through every
> |
> | chemical combination which could be usd to combat the virus until the
> | correct combination is found and a vaccine would be created. He
> | suggested that, although perhaps not in our lifetimes, but maybe our
> | childrens', any new virus which would appear would be routinely
> | eliminated by computer-generated vaccines. Part of the problem, he
> | suggested, is developing fast enough computers to run through all the
> | combinations. His description reminded me of Microsoft's anti-virus crew
> |
> | working day and night for a couple of days sometimes to produce a patch
> | when e.g. a significant new internet-related virus would be introduced.
> | What do you
> | think of his theory? Do you think that disease of any kind will be wiped
> |
> | out by computers by the end of the next century?
> |    Any comments or response related to this subject would be immensely
> | appreciated.
> | Bruce Compton
> | bcompton@quik.com
> |
>
>

I am just wandering in for the day, so don't expect any further response.

Pierre wrote in message <814hkq$965$1@news2.isdnet.net>...
>I agree with Tyson. Computer are more and more helpful. but we are still
not
>able to calculate reliably the 3D structure of a single protein. Thus,
>saying that one day we will be able to calculate a vaccine with a
>supercomputer is science fiction. May be we will. May be not. Notice also
>that it is a reductionist/determinist dream that might be totally
irrelevant
>to biology. For example, will the same supercomputer be able to calculate
>the future evolution of man ?

Progress is being made in predicting the 3-D structure of proteins.  By the
end
of next century that will not be a problem.  However, there are more
problems than
that in fighting disease.

The least of which is finding out which protein is being affected by the
disease.

Computers are used heavily now in what is called rational drug design:

Approach 1 - active site not known

1) Take a known drug that works.
2) Build a model of the active site where the molecule
determines its shape and charge distribution of your model site.
For example, if the drug has a hydrophobic chain, there probably is
a hydrophobic pocket at a corresponding position in the active site.
3) Make changes to the drug.  From the effects, one can refine the model
shape and charge distribution of the active site.

Approach 2 - active site structure known

1) Make a theoretical combinatorial library of molecules that bind to
the site.
2) Compute the binding of each.
3) Examine the shapes and charge distributions of the best, try different
types of drugs that will give similar ones.

What can be done quite nicely (although there is room for better
quantitative accuracy that will also come) is computing of binding
to an active site.

However, just because a molecule has the best binding ability does not
mean it is the best drug.  It also has to *get to* the protein (or DNA, or
RNA),
not be metabolized, the treatment has to depend on strength of
binding to the active site (best for competitive inhibition), and it should
not
bind to other active sites as well, which can cause side effects.

It is a long, tedious process.

One way to try to reduce the side effects is to introduce rigidity into the
molecule.  This would work best where a flexible molecule takes one
shape in binding to the active site desired, and another in binding to the
site which causes side effects.  If you can make a drug with the rigid
conformation close to the first, it will not bind as well to the second.
Rigidity can be introduced primarily by using rings instead of chains.

Combinatorial chemistry relies more on automation rather than
*calculations*,
although computer data analysis and process control is required.

I have heard this approach called irrational drug design.  There is no clear
advantage of irrational to rational.  The major drug companies use both.

Experiments will always have to be done in the foreseeable future,
although theory will help in both the screening of compounds AND
in the study of the basic processes.  Theory is also a major component
of the latter.

Tracy P. Hamilton

What is the role of contingency/probability in protein folding ? If one
chain has many possible foldings, each affected with a given probability
amongst the population of molecules (like in evolution/population genetics),
is it possible to calculate all the variations ?

Tracy P. Hamilton <chem013@uabdpo.dpo.uab.edu> a �crit dans le message :
816k1b$fc5$1@SonOfMaze.dpo.uab.edu...
> I am just wandering in for the day, so don't expect any further response.
>
> Pierre wrote in message <814hkq$965$1@news2.isdnet.net>...
> >I agree with Tyson. Computer are more and more helpful. but we are still
> not
> >able to calculate reliably the 3D structure of a single protein. Thus,
> >saying that one day we will be able to calculate a vaccine with a
> >supercomputer is science fiction. May be we will. May be not. Notice also
> >that it is a reductionist/determinist dream that might be totally
> irrelevant
> >to biology. For example, will the same supercomputer be able to calculate
> >the future evolution of man ?
>
> Progress is being made in predicting the 3-D structure of proteins.  By
the
> end
> of next century that will not be a problem.  However, there are more
> problems than
> that in fighting disease.
>
> The least of which is finding out which protein is being affected by the
> disease.
>
> Computers are used heavily now in what is called rational drug design:
>
> Approach 1 - active site not known
>
> 1) Take a known drug that works.
> 2) Build a model of the active site where the molecule
> determines its shape and charge distribution of your model site.
> For example, if the drug has a hydrophobic chain, there probably is
> a hydrophobic pocket at a corresponding position in the active site.
> 3) Make changes to the drug.  From the effects, one can refine the model
> shape and charge distribution of the active site.
>
> Approach 2 - active site structure known
>
> 1) Make a theoretical combinatorial library of molecules that bind to
> the site.
> 2) Compute the binding of each.
> 3) Examine the shapes and charge distributions of the best, try different
> types of drugs that will give similar ones.
>
> What can be done quite nicely (although there is room for better
> quantitative accuracy that will also come) is computing of binding
> to an active site.
>
> However, just because a molecule has the best binding ability does not
> mean it is the best drug.  It also has to *get to* the protein (or DNA, or
> RNA),
> not be metabolized, the treatment has to depend on strength of
> binding to the active site (best for competitive inhibition), and it
should
> not
> bind to other active sites as well, which can cause side effects.
>
> It is a long, tedious process.
>
> One way to try to reduce the side effects is to introduce rigidity into
the
> molecule.  This would work best where a flexible molecule takes one
> shape in binding to the active site desired, and another in binding to the
> site which causes side effects.  If you can make a drug with the rigid
> conformation close to the first, it will not bind as well to the second.
> Rigidity can be introduced primarily by using rings instead of chains.
>
> Combinatorial chemistry relies more on automation rather than
> *calculations*,
> although computer data analysis and process control is required.
>
> I have heard this approach called irrational drug design.  There is no
clear
> advantage of irrational to rational.  The major drug companies use both.
>
> Experiments will always have to be done in the foreseeable future,
> although theory will help in both the screening of compounds AND
> in the study of the basic processes.  Theory is also a major component
> of the latter.
>
> Tracy P. Hamilton
>
>
>
>

Pierre wrote in message <818dle$2jee$1@news4.isdnet.net>...
>What is the role of contingency/probability in protein folding ? If one
>chain has many possible foldings, each affected with a given probability
>amongst the population of molecules (like in evolution/population
genetics),
>is it possible to calculate all the variations ?


[snip my previous post]

One would not be able to go thorough all possible protein conformations.
I *believe* (I am no protein folding expert, but a theoretician in a more
fundamental sense) that current approaches are more empirical.
Predict secondary structure (alpha helix, beta sheet, random coil) from
part of the amino acid sequence, tertiary structure (overall shape) is from
a different database, but similarly empirical.  Both are correct about half
the time now, last I heard.

A group was able to predict the sequence of a protein that would be
the same shape as one of the zinc finger proteins, except without zinc!
Makes one wonder why zinc fingers have zinc...

Theory does currently play a large role in constraining structures,
particularly
NMR ones (solution structures based on H-H distances).  I don't have a
good feel for what would happen if you applied one of the good protein
force fields to the superoxide dismutase enzyme (or the mutant that
has been identified with inherited ALS which has a more exposed
active site).

If I were to model the active site, I would probably put some geometric
constraints on the active site to keep it in the neighborhood for at least
some calculations.

Tracy P. Hamilton