- To discover new therapeutic uses of
existing drugs, scientists and pharmaceutical industry employ traditional
screening methods against specific desired targets.
- Traditional screening methods have
certain limitations, namely that they cannot identify processes involving
more than one enzyme allosteric agent.
- New drug screening method in the
presence of known allosteric enzyme inhibitor found to be superior and
increases the possibility of new drug discovery for several diseases.
New CoSPI screening method tests potential
drugs or compounds in the presence of known allosteric inhibitor of the target
enzyme, thereby improving chances of finding drugs that can alter enzyme
activity, which is not possible with existing traditional screening methods.
The current research project was undertaken by the Francis Crick Institute
and University of Manchester
, and the findings of the study appear in the
August edition of Nature Communications
'Uncoupling conformational states from activity in an allosteric enzyme'
‘Compound screening in the presence of known inhibitor (CoSPI) helps identify drugs capable of altering enzyme activity, which is impossible with traditional screening methods.’
Test Compound In The Presence Of Inhibitor - Reason For Study
Finding new drugs from scratch is an elaborate process and costs millions of
laboratories and pharmaceutical industry resort to screening thousands of existing compounds by traditional methods for
new undiscovered activity
against emerging or existing diseases and
Traditional screening involves testing
the drug against a specific enzymatic target and analyzing observed effects such as enzyme activation or inhibition, or binding to
the target protein
. Depending on the observations, these compounds will be further evaluated for safety and efficacy
before being used in the clinic.
However, traditional screening methods
have certain limitations in that they cannot
that are capable of altering enzyme activity when more than one allosteric
agent is present
, thus missing out on the opportunity of
identifying several such agents for further evaluation and clinical use.
Current research team has developed a
method of testing compounds against specific targets, termed CoSPI
by adding a known allosteric inhibitor, which
helps to identify compounds that alter enzyme activity and thus improve chances
of finding potential treatments
for several new diseases.
Screening In The Presence Of Allosteric Inhibitor - New Drug Screening Method
- Since drug
resistant tuberculosis is emerging rapidly, the team chose to test the CoSPI method on a compound hoped to be useful
against Mycobacterium tuberculosis, the bacteria that causes tuberculosis.
- To test the new screening method,
the team employed an enzyme present
in tuberculosis (TB) bacteria known to speed up the first step in
histidine synthesis- an amino acid essential for humans. They tested
potential drugs/compounds on it in the presence of its substrates after the addition of a known allosteric inhibitor of this
- During the screening, they identified an allosteric drug/compound
that successfully competes with the inhibitor, drastically enhancing
the activity of the enzyme. Compounds such as this allosteric activator prevent proper regulation of metabolic
pathways and deplete energy from bacteria until they die.
- Importantly, since humans do
not naturally have this enzyme -
we obtain histidine only from our diet, it is possible that this compounds
could be used to kill tuberculosis bacteria without damaging human cells, thereby opening up the possibility of
a new and safe drug for tuberculosis and may be other infections as
involve mixing a specific drug/compound
with an enzyme and its substrates, and therefore cannot delineate effects due to the presence of more than one
"Allosteric enzymes have important
functions in all living things from bacteria to humans, and now we have an
improved way of finding new drugs that could work by targeting them," says
Luiz Carvalho, Group leader at the Francis Crick Institute.
Pathways, Enzymes, Allosteric Activators And Inhibitors - In Brief
- All cellular metabolic pathways
require enzymes (proteins that accelerate chemical reactions). These
enzymes act upon their substrates (molecules that are altered by enzymes)
resulting in the synthesis of substances that are useful for the body,
breakdown of certain molecules and for provision of energy.
- These pathways have to be strictly
regulated, and therefore the enzyme activity in these pathways have to be
consequently adjusted to supply the right amount of substrate and to
generate the right quantity of the desired end product.
- Allosteric compounds modify enzyme
activity by making enzymes bind to their substrates either more or less
efficiently, or by increasing or decreasing the rate of the reaction.
- Compounds that enhance enzyme
efficiency are known as allosteric activators, while those that decrease
it are known as allosteric inhibitors.
- When many allosteric compounds are
present, they can either compete with one another, so that one of them has
a dominant effect on enzyme activity or may complement each other to
produce a greater effect.
As stated above, the new CoSPI screening
method developed by the research team enables identifying drugs/compounds with
enzyme activity altering property (by adding a known allosteric inhibitor), and
improving chances of drug discovery.
To conclude with the remarks of one of
the authors, Cesira de Chiara, a scientist at the Francis Crick Institute,
"Our method allows us to find out early on how compounds interact to
change enzyme activity,". We can find out more information in fewer
experiments, which helps accelerate the drug discovery process."
- Joćo P. Pisco, Cesira de Chiara, Kamila J. Pacholarz, Acely Garza-Garcia, Roksana W. Ogrodowicz, Philip A. Walker, Perdita E. Barran, Stephen J. Smerdon, Luiz Pedro S. de Carvalho. Uncoupling conformational states from activity in an allosteric enzyme. Nature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-00224-0