G'day Athel;
On 9 Jan 2002, Athel Cornish-Bowden wrote:
[...]
> Most of the top companies are not generating in-house the new products
> needed to sustain [their] rates of growth"
[...]
Drug design, as it is, is a falicy and this is why the pharm industries
have problems. They are far too big now and swallowing each other up to
try and buy a profit because they cannot produce enough actual new product
onto the market that are effective. They must grow at a massive rate to
remain viable and so sadly the new pharmaceuticals are underdeveloped in
an attempt to get something onto the market and turn some profit. In the
"journal" Drug Discovery Today (which is an interesting rag that helps
keep lazy literature readers abreast of broad changes and discoveries),
they make these facts painfully obvious.
The more times you make a virtual library and bias it with experimental
designs, the more you find your "active" compounds are lipophilic messes,
as these things are more orally and cellularly bioavailable. This is why
small companies are springing up using "sugar chemistry" etc, they're
changing the scaffolds. If someone can come up with a good liposomal
delivery system or somesuch, suddenly peptides and substrates are viable
drug candidates - and then it will be open slather. The problem with this
is patentability. Who patents a substrate? Can you even do it?
So alternate "out-there" therapies are being looked at. Things like
proteins as therapeutics, antisense phosphoamidate nucleotides, peptide
nucleic acids etc etc. My thought is it will be the ballsy little company
that doesn't care about patenting that will make millions in the future
selling peptides as therapeutics. Peptides have been evolutionarily
selected over eons of times and under conditions we can only guess at but
cannot fathom - how small minded is it to assume we can make molecules to
do better?
Then, of course you have the issue of "the system". Things existing in
compartments or interacting in different ways within different
environments makes the whole process of drug design a joke.
> The conclusion is more optimistic: "Genomics will deliver in the end", but
> there isn't actually much offered in the way of evidence to justify this
> optimism. Wishful thinking rules, as always.
I think genomics can only ever be part of the answer. It's a quick
solution to a complex question, but is it correct? Take G-proteins for
example. If you try and pump up the expression levels or control the
expression, you find your cells die, so you cannot easily use a microarray
to see what is switched on and elucidate the pathway. The expression is
normally so tightly regulated that it is an amassing of certain
proteins (in different locations) that is actually important. Perhaps
the genes aren't upregulated at all! Perhaps even proteomics will only
tell us part of the answer, or maybe Rodbell was right in 1991 when he
said "Nature cannot simply be fathomed by knowing its chemical and
physical composition. The living process has evolved far beyond our
knowledge of physics and chemistry. Understanding the organization and
integration of all cellular information processing systems presents
challenges that certainly will not be met in my lifetime, and perhaps
never."
Len...
