Drugs either bind to the substrate or cofactor binding site but which one is better to target?
I guess targeting cofactor binding would give us an opportunity to fine tune the signaling pathway.At right concentration allosteric inhibitors might act in a context specific and target specific manner.In most scenarios it is not advisable to completely shutdown a signaling pathway and therefore i guess allosteric inhibitors might be a great choice to avoid side effects of a drug.
Dr. Krishanand is correct in saying that it is not advisable to completely shut down a pathway...But, If a drug has to give a strong therapeutic effect, it is necessary to target the active catalytic site or the substrate binding site. Targeting allosteric sites would not give strong irreversible shutdown of the enzyme. Please note that even if the enzyme is fully inhibited, there are often related enzymes that can compensate, and keep the pathway partially active! A good example of this compensation are RTK's (receptor tyrosine kinases) in many tumor cells. This is what leads to drug resistance. Hope this helps!
Sorry, I need say a few things about inhibition. First, competitive means that the substrate and inhibitor bind the same enzyme form. For allosteric, the inhibitor does not have to bind the cofactor site. Allosteric just means other site. If you do interfere with the cofactor, this could have implications for affecting huge numbers of enzymes that have the same cofactor. But then there are mechanism based inhibitors like chloro alanine that affects both substrate binding and the cofactor PLP, but these types of inhibitors tend to be toxic. There are drugs that are not always competitive inhibitors. Some enzymes have more than one substrate, ie the kinases, that use ATP and a peptide substrate, so they could be competitive for one substrate but non competitive, uncompetitive against another substrate. Methotrexate is an antifolate drug and is highly, toxic. HIV proteinase inhibitors are reversible and competitive inhibitors and are not too toxic., etc.
Statins or HMG-CoA reductase inhibitors are competitive inhibitors to reduce blood cholesterol level. They have been quite successful and widely accepted now.
There is not possible to give a general answer, each enzyme or receptor has to be in-vestigated separately.
Maria Wollemann
As Dr. Maria says, each case should be considered carefully. But, there maybe some ground rules....For e.g., If an enzyme is part of a gene family, then its active site is conserved, and targeting active site of 1 family member may be futile. But, if an enzyme is not part of a family, or if its an isoform with tissue specific expression, then one could design an inhibitor against active site and this should work . Hope this helps!
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