Download Lecture 4. The Screening Hypothesis.

Lecture 4 – the Screening Hypothesis
explains why the world goes round!
At the end of this lecture you should know:
• Why the chemical co-evolution model to explain NP
diversity is wrong!
• How another evolutionary model, the Screening
Hypothesis, provides a much more probable
evolutionary scenario to explain not only NP abundance
but also the properties of NPs.
 That potent and specific biological activity is a
rare property for a molecule to possess.
 That because potent, specific biological activity is
a rare property, organisms gaining fitness through
making biologically active NPs must have evolved
metabolic properties that enhance the chances of
making and retaining chemical diversity
• The chemical co-evolution model – widely
accepted for 40 years
Phytoalexins
• The chemical co-evolution model – widely
accepted for 40 years
Allelopathy
• The chemical co-evolution model – widely
accepted for 40 years
..“Volatile metabolites of
Lycopersicon species are of
interest because of their roles in
tomato flavour and in host
defense against arthropod
herbivores ..” (Colby et al.,
1998).
• Why is the chemical co-evolution model wrong?
Because it cannot explain why
most NPs seem to possess, at
best, very weak biological
activity.
Thus only a very small % of
the known NPs have ever had
any role ascribed to them.
The fragmentation of the
subject hides this fact.
• Why is the chemical co-evolution model wrong?
The chemical co-evolution model is based on
the idea that every NP, is, or has been at some
stage in evolution, biologically active.
PM
B
C
D
E
• Why is the chemical co-evolution model to explain NP
diversity wrong?
Because potent biological activity is a rare property for any
one molecule
Evidence
• Study 1. 400,000 microbial cultures were screened over 10 a year period
and only three utilisable compounds were found
• Study 2. 21,830 isolates screened in one year to give 2 possible
compounds
• Study 3. 10,000 microorganisms were screened but only one clinically
effective agent was found
This low “hit rate” is not what the chemical co-evolution model
predicts. The co-evolution model predicts that organisms should
contain a few highly active compounds. The reality is that they
• Why is the chemical co-evolution model to explain NP
diversity wrong?
Because biological activity is a rare property for any
one molecule.
Evidence
In this respect NPs do not differ
from synthetic chemicals.
• Tens of thousands of chemicals
are “screened” every day by
pharmaceutical companies in their
search for new drugs. The “hit
rate” is very low. < 1 in 1000.
• Why is the chemical co-evolution model to explain
NP diversity wrong?
Because biological activity is a rare property for any
one molecule
Evidence
•Tens of thousands of chemicals are
“screened” daily for agrochemical
use – insecticides, herbicides,
fungicides, etc.. The “hit rate” is very
low. < 1 in 1000.
Nearly 100.000 different synthetic
organophosphorus derivatives were
made in a search for insecticides but
<100 commercially useful products
were found.
Why is potent specific biological activity rare?
At low concentrations, a reversible, non-covalent interaction between a small
molecule and a protein only occurs if the small molecule fits precisely into the
protein structure
Why is potent specific biological activity rare?
At low concentrations, a reversible, non-covalent interaction between a small
molecule and a protein only occurs if the small molecule fits precisely into the
protein structure
• Why is the chemical co-evolution model wrong?
Because it cannot explain why most NPs seem to
possess, at best, very weak biological activity and that
means that ……..
PM
B
C
D
E
The chance of every compound in a sequence
possessing potent, specific biological activity is so
low that is very hard explain why the pathways have
evolved …
The balance between opportunities for cost savings and
enhanced fitness changes as the biosynthetic chains
lengthens. Once D nolonger has a lasting benefit, there are
more opportunites to gain immediate finess benefits by cost
reduction than there are opportunities to gain fitness by the
low probability event of making biologicall active E
• Why is the chemical co-evolution model wrong?
Because it cannot explain why most NPs seem to
possess, at best, very weak biological activity and that
means that ……..
PM
B
C
Worse still, the organism that is
selected against by B will
evolve to cope with B
Two basic stragtegies seem common.
1.
2.
The organism alters the receptor protein so that B fits less
well in its binding site.
The organism reduces the effective concentration of B by not
taking B up, by breaking down B, pumping it out of the cell or
sequestering B in some way
Hence a chemical similar to B, like the next compound C is
facing a preadapted organism capable of handling molecules
sharing chemical features with B
How to improve the odds of making a rare biologically active pr
Old paradigm – one enzyme, one productNew paradigm – one enzyme, many prod
How low enzyme substrate specificity could help improve fitnes
One mutation could generate many new products
The Screening Hypothesis – key
points
Based on overwhelming evidence that potent, specific
biological activity is very rare
Can explain why most NPs are not impressively
biologicall active
Can explain why a very few NPs are very highly
biologically active
Can explain why weird types of activity occur in unexpected places
e.g. why the bark of Taxus contain an anticancer drug
The Screening Hypothesis Predictions about the
metabolism making NPs
Many enzymes involved in NP biosynthesis will have a broad substrate toler
Some enzymes might participate at more than one step of a pathways
Some enzymes may produce multiple products - chemical
reactions or rearrangements will be used to generate chemical
diversity
Metabolic grids will be found