Comments (3)
I'm gathering my thoughts about this - I'll likely answer after the July 4th holiday...
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This is an interesting question.
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In essence, you are stating that kinetics will be most important to consider for high-vulnerability targets, since kinetic selectivity and prolonged effects will only be useful for targets with high vulnerability. In contrast, low-vulnerability targets will more quickly recover from treatment, regardless of the binding/unbinding kinetics. Therefore, for low-vulnerability targets, we are forced to consider the thermodynamics as being of primary importance when considering selectivity and efficacy.
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You express doubt that SEEKR2 will be useful for a target unless one can confirm that it is a high-vulnerability target.
Here are my answers:
First, I'd like to point out that SEEKR2 can obtain estimates of thermodynamics quantities in addition to kinetics (the K_D is a thermodynamic quantity), so SEEKR2 is equally likely to be useful for either high- or low-vulnerability targets. In addition, SEEKR2 doesn't just provide k_on, k_off, and K_D, but also molecular-level details about the binding process. (We are actively working on tools to leverage SEEKR2 results to extract molecular details of binding, by the way.)
Assertion 1 seems valid. However, I'm not sure how often the vulnerability of a target is measured experimentally, or whether it can be effectively modeled computationally. In theory, one could perform an experiment and make plots similar to figure 4 in Tonge 2018 to obtain the vulnerability, But then, at least for that inhibitor-target pair, one has already measured the kinetics, and SEEKR2 would not add any additional kinetics information. However, once the target's vulnerability is known, one could use that knowledge when discovering new inhibitors. It would make sense for a pharma company, after identifying a target, to measure that target's vulnerability in order to decide whether to focus on favorable kinetics or thermodynamics.
I don't believe that assertion 2 is valid, however, because SEEKR2 can obtain thermodynamics of binding, as well as kinetics. However, without knowledge of the vulnerability of the target, one may not know whether to focus on favorable kinetics or thermodynamics of an inhibitor.
I'd be interested to continue discussing and to hear any further thoughts on the matter.
from seekr2.
I'm going to close this issue for now.
from seekr2.
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