Drugs that act as transition state inhibitors are known to have high binding affinity to their target enzyme, possessing binding tighter millions times than the substrate, a property inherent from the mechanism of the enzymatic catalysis proposed by Linus Pauling.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560411/
This is attractive and I wonder if there any reasons, rather than selectivity consideration, by which the design of a transition state analogue inhibitor for some enzyme would be impossible, useless or of negative outcomes ?
waiting for your experienced and logical opinions ..
Regards ..
One likely reason that there are not more drugs that are transition state inhibitors of their enzyme targets is that the transition state is not "drug-like."
For example, if the substrate is a highly charged molecule like a nucleotide, or a nucleic acid, the transition state of the reaction will also contain that charge. Such a molecule will lack oral bioavailability because of its charge, and also may not be able to permeate into cells when administered intravenously. You may be able to design a transition state analog that inhibits the enzyme, but it won't be any use as a drug. So, consider the physical properties (drug-likeness) of the substrate(s) when deciding on an enzyme for which to design a transition state analog.
You also have to consider whether the reaction is one for which it is feasible to design a transition state analog, regardless of the physical properties of the substrate. Many enzyme reactions simply don't lend themselves to this approach.
Some drugs that are enzyme inhibitors are mechanism-based inhibitors, rather than transition state analogs. They usually resemble the substrate. The enzyme forms an irreversible covalent bond with the compound as a result of the catalytic mechanism. Another term for this is "suicide substrate." A good example is penicillin. Rather than high binding affinity, mechanism-based inhibitors may achieve high potency by a high reaction rate and accumulation of inhibition over time due to irreversibility.
One likely reason that there are not more drugs that are transition state inhibitors of their enzyme targets is that the transition state is not "drug-like."
For example, if the substrate is a highly charged molecule like a nucleotide, or a nucleic acid, the transition state of the reaction will also contain that charge. Such a molecule will lack oral bioavailability because of its charge, and also may not be able to permeate into cells when administered intravenously. You may be able to design a transition state analog that inhibits the enzyme, but it won't be any use as a drug. So, consider the physical properties (drug-likeness) of the substrate(s) when deciding on an enzyme for which to design a transition state analog.
You also have to consider whether the reaction is one for which it is feasible to design a transition state analog, regardless of the physical properties of the substrate. Many enzyme reactions simply don't lend themselves to this approach.
Some drugs that are enzyme inhibitors are mechanism-based inhibitors, rather than transition state analogs. They usually resemble the substrate. The enzyme forms an irreversible covalent bond with the compound as a result of the catalytic mechanism. Another term for this is "suicide substrate." A good example is penicillin. Rather than high binding affinity, mechanism-based inhibitors may achieve high potency by a high reaction rate and accumulation of inhibition over time due to irreversibility.
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