tag:blogger.com,1999:blog-9633767.post1668042944704301983..comments2024-03-25T09:11:17.877-07:00Comments on The Curious Wavefunction: Kinetics in drug discovery: The neglected child?Wavefunctionhttp://www.blogger.com/profile/14993805391653267639noreply@blogger.comBlogger7125tag:blogger.com,1999:blog-9633767.post-73467405877603801362012-09-20T12:31:20.244-07:002012-09-20T12:31:20.244-07:00Then the question would be: Is the off-target aff...Then the question would be: Is the off-target affinity of a compound determined more by the enthalpy & entropy changes associated with binding to the target than by its physicochemical properties? There is also the question of the strength of the correlation between promiscuity and lipophilicity...<br /><br />Back to "wrong type of snow" and I'll give you the link since my version was abbreviated in the interest of space. I'll never cease to be amazed by the excuses that rail travel in the UK leads to such as "leaves on the track". My personal favourite was the train driver who had to return to Birmingham because he got "lost". <br /><br />http://en.wikipedia.org/wiki/The_wrong_type_of_snowPeter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-12027090755353690952012-09-20T07:44:52.081-07:002012-09-20T07:44:52.081-07:00So if I understand you correctly, you are asking t...So if I understand you correctly, you are asking the following interesting question; how would you distinguish two ligands with the same binding energy but different enthalpic vs entropic contributions? I think you are right that their on-target effect would probably be the same. The entropically driven ligand might be lipophilic however and this would likely contribute to a bad off-target profile.<br /><br />Nice quip about the snow. I tried something similar last winter, but my wife didn't buy it.Wavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-79029822572688520732012-09-18T10:38:50.942-07:002012-09-18T10:38:50.942-07:00The issue for me is whether or not the enthalpy an...The issue for me is whether or not the enthalpy and entropy changes associated with binding have any relevance to drug action. Drugs need to bind in order to act so the changes in Gibbs free energy associated with binding will be relevant to drug action. However, it is much harder to make an analogous case for the relevance of changes in the entropy and enthalpy associated with binding. If one is going to argue that the thermodynamic signature of binding is relevant one has to show how systems are capable of discriminating between compounds with different thermodynamic signatures. When invoking thermodynamics it is important to describe phenomena using the appropriate thermodynamic quantities. Enthalpy changes will certainly be relevant when manufacturing drugs and, since synthetic reactions used in process work are often irreversible, free energy changes will not usually be known.<br /><br />The focus on 'enthalpic binders' reminds me of the excuses made for train delays by the old British Rail. "Snow on the line", said the BR spokesperson. Further interrogation prompted the iconic response: "Wrong type of snow". Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-20318286476638610222012-09-18T07:25:45.471-07:002012-09-18T07:25:45.471-07:00I think the papers by Freire illuminated something...I think the papers by Freire illuminated something that's kind of obvious but also hard to control, namely the fact that entropy is much easier to optimize than enthalpy. I think his analysis is most valuable in the rare exceptions where the converse might be true, in which case it could be very valuable to do ITC early on since you could then optimize entropy with scant effort (perhaps by tacking on a hydrophobic aromatic group). Otherwise you might be misled in thinking that you have to optimize enthalpy and actually move away from optimal interactions with the target.Wavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-13726282345680085772012-09-18T07:24:56.362-07:002012-09-18T07:24:56.362-07:00Yes, that's an important point, knowing the di...Yes, that's an important point, knowing the differences between in vitro closed systems and in vivo open systems; the example of a membrane protein sounds especially relevant. You would expect this difference to affect the k(on) rate more though since k(off) depends mainly on the intermolecular interactions. You are probably right that ITC is still not high throughput enough, one reason why drug companies have been reluctant to use it on a regular basis. SPR does seem amenable to higher throughput, especially instruments with 96 wells.<br /><br />On a more general note though, I really liked the second article since it makes a very cogent comparison of the lack of biochemical sophistication in pharma compared to academia where biochemistry is wielded both as a fine scalpel and as an earth mover to uncover all kinds of fascinating details about proteins. Wavefunctionhttps://www.blogger.com/profile/14993805391653267639noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-20860443287307895042012-09-18T07:06:31.636-07:002012-09-18T07:06:31.636-07:00Binding kinetics need to be seen in the pharmacoki...Binding kinetics need to be seen in the pharmacokinetic context if one is arguing for their relevance to Drug Discovery. If binding is faster than distribution then you probably don't need to worry about it too much. It can be difficult to establish the importance of off-rates especially when the kinetics are not separated from the thermodynamics. Put another way, the standard free energy of binding usually contributes to the activation energy for dissociation. The other thing to remember is that for fixed affinity, a slow off-rate means a slow on-rate and equilibrium will not have been attained before the start of the elimination phase.<br /><br />I remain unconvinced that measuring enthalpy and entropy changes associated with binding are particularly relevant to Drug Discovery. These parameters are certainly of scientific interest (as are the volume changes associated with binding) and may ultimately help us make better predictions of affinity. My routine challenge to those who assert the benefits of 'enthalpically-driven' binding is to ask how isothermal systems (i.e. humans taking the drugs) 'sense' these benefits. Peter Kennyhttps://www.blogger.com/profile/12180360326821860667noreply@blogger.comtag:blogger.com,1999:blog-9633767.post-80521549545060479962012-09-17T17:22:16.413-07:002012-09-17T17:22:16.413-07:00Thanks for the adds to the reading list - while I ...Thanks for the adds to the reading list - while I have the general biochemistry background, I figure it's helpful that I start picking up some things of more direct relevance to pharma/drug discovery.<br /><br />I suppose one issue is variation between on/off rates measured <i>in vitro</i> and <i>in vivo</i>. I could imagine that - for example - this problem could easily arise if you've got a target protein that is membrane associated but the test tube assay involves a soluble construct of said protein. Perhaps that ligand is hydrophobic enough that it might partition into the membrane to some extent (or something). <br /><br />Regarding ITC - how high-throughput is that technology? My impression is that while strides have been made, it's still not quite at the level of the label-free biosensors out there (I tried my hand at SPR a while back, and even with an older system, I was still able to knock out a number of samples/replicates without too much difficulty). <br /><br />MJhttps://www.blogger.com/profile/02796378432680640144noreply@blogger.com