The concept of molecular complexity was articulated in a 2001 article which is oen of favorites. The basic idea is simple. Complex molecules are expected to bind more tightly to their targets than less complex molecules provided that they achieve an optimal fit. The sting in the tail is that the probability of achieving that optimal fit decreases with molecular complexity.
Let's put it all together. Take a look the plot below which corresponds to Figure 3 in the featured article and please accept our apologies for the poor quality graphic. The mauve line is the probability of measuring binding, assuming that the compound does indeed bind and the blue line is the probability of matching one way. The yellow line is the product of these two probabilities and represents the probability of what the authors term a useful event. We are not convinced that binding more than one way is not useful. However this is a minor detail and it has no qualitative effect on the the shape of the all important yellow curve. It has a maximum.
Molecular complexity ====>
What does this picture tell us? If you're randomly testing compounds, you need to get the complexity just right. If the compounds have too few molecular recognition elements, they can't bind tightly enough to be detected in the assay. Unless of course you've got a special assay (e.g. protein-detect NMR) which is the essence of fragment screening. Go to the other extreme, however, and you'll find that a molecule with lots of molecular recognition elements is unlikely to be able to deploy them all simultaneously. So you screen at low complexity and and then make your leads more complex, increasing their potency against their intended target, all the while decreasing their chances of binding to the anti-targets. Isn't Drug Discovery easy? There are still unanswered questions. What is low complexity? Simple, it depends on your assay. But how can that be, Master? Surely complexity is a purely molecular property. That is true, Grasshopper, complexity is indeed molecular but its degree is assay-dependent.
And you haven't even told us what molecular complexity is! What does this load of bullshit have to do with the contribution of hydrogen bonds to binding energies? Patience, Dear Reader, all will be revealed. Molecular complexity can take many forms depending on whether you're trying to synthesise the molecule or intepret its NMR spectrum. Bigger molecules tend to be more complex because there are limits to the number of chiral centers and spiro ring fusions you can accommodate in a molecule with a molecular weight of 42. In molecular recognition, hydrogen bonding groups are important elements of molecular complexity. This is so because their interactions with target and aqueous solvent are highly directional. The solvent is more adaptable than the geometrically constrained target, but not infinitely so. If you're going to yank all of those hydrogen bonding groups out of water, you'd better have some binding partners lined up in the protein. In exactly the right places.
By now you're thinking this all sounds very Second Law, very Maxwell's demon. And that's exactly what you should be thinking so congratulations getting there. It is a privilege to write for such clever readers. Molecular complexity is about entropy, even before you start to think about comformational flexibility. And that bring us back to the binding of glucose analogs to glycogen phosphorylase. Glucose has 5 hydroxyl groups which interact with the protein and most of these form hydrogen bonds to more than one residue. So the probability that evry single one of these hydrogen bonds will be of optimum geometry is low.
Now let's take a look at what happens when you get rid of one of the hydroxyl groups. The hydrogen bonds for the 4 remaining hydroxyl groups are no longer compromised by the geometric requirements of the hydroxyl group that you just zapped. We expect, on the basis of molecular complexity, that removal of one hydroxyl group will strengthen the individual contributions of the others. If you removed hydroxyl groups one at a time, their apparent contributions to binding energy would depend on the order in which they were removed and, by implication how many had already been removed.
This brings us to the conclusion of our discussion. Do you believe that the effect on binding, of removing of one of glucose's 5 hydroxyl groups will accurately predict an upper limit for the contribution of a neutral-neutral hydrogen bond? It is not for us to say for we are but simple folk. So just take this pebble from my hand and it will be time for you to go.
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