So let's take a step back and consider what happens when a small molecule, this thing in purple that's currently depicted on the left as being in solution. Binds to a drug target, a protein, and in this case we are showing the proteins schematically as an invagination on the surface that is that is full of water molecules. And what we know from a series of physical chemical studies. Is that the water that organizes itself around the small molecule and the water that organizes itself in this binding site on the surface of the pro team has low endtropy meaning that there, there quite well localized. They're not bouncing around in solution. When you form the complex depicted on the right there, many of these water molecules are extruded out into the bulk solvent. And there's a big increase in the entropy of the system. The reason that the water molecules form organized structures around both. The small molecule in the protein is due to the hydrophobic effect. An effect, that when you expose carbon atoms on the surface of a protein or on the surface of a small molecule, the water forms cages around them because it can't hydrogen bond to the to the carbon atom. And, its, its this hydrophobicity, this lipphobicity that helps contribute to drug binding because when the drug binds, you get a big increase in the entropy of the system. And you recall that the Gibb's free energy describing the strength of the interaction between the small molecule and the protein is given in terms of the sum of the enthalpy and the entropy term, the minus t delta s. And the lower the number the better the delta G, the stronger the binding. So, as your entropy goes up, strength of binding goes up. One way of doing that is to have a very, very greasy compound. The problem with such greasy compounds is that they bind to lots of proteins and then you get unwanted off target binding and you get. You know what we would call, colloquial side effects from medications. So just bear that in mind as we go through this. So, I've already given you a preview, preview of why lipophilicity matters in the drug discovery enterprise when one is working with small molecules. The the exercise that was published by Leeson and Springthorp in 2007 showed that promiscuity of binding to off targets is a sigmoidal function, meaning an s shaped curve of this measure of lipophilicity log p. Does anyone know what p is? Not permeability, not pressure, it's the partition coefficient of of a small molecule between octanol and water. So between a a polar and a non-polar environment. And the c, the little c here means that it's the calculated logarithm of this partition coefficient. The lower that number, the more polar the compounds are. The higher the number, the more hydrophobic the compounds are. When the compounds are more hydrophobic they bind indiscriminately to off targets and you have promiscuous binding. And and the surprise that came from this analysis from Kohler and Landis is there is such a dramatic increase in promiscuity, as a function of lipophilicity as you move from left to right. So clearly you want to have a c log p of less than three. recall that Li, Lipinski said he wanted to see log p of less than five. Permeability and being a drug, meaning have, having a minimum of unwanted side effects are two very different things. So what what chemist have done as they've been trying to understand how best to go from a starting point for drug discovery to a drug. is to develop a set of, of metrics that help guide the the medicinal chemistry helped guide the modifications they are going to make to the small molecule to optimize binding. And at the same time, be careful not to introduce too much unwanted binding, too much promiscuity. So, again from this Leeson and Springthorp paper, you've got the lipophilic ligand deficiency metric which is a measure of potency versus grease. And the goal is to add potency, add strength of binding without grease. And so, the formulism here is that the, the LLE is minus the LOG of the IC 50 minus C LOG P. Can anyone tell me what the IC 50 is? It's the concentration at which 50% of the target activity is prohibited, exactly, yep. And, if if one takes the logarithm that, of that, you get the, the binding constant. What we are trying to do here is to normalize potency for lipophilicity so minus the log of the IC50 minus cLogP, if you put in some exemplar values and say you want your small molecule to bind very tightly. Meaning better than 10 nanomolar IC50, and want, you want your cLogP to be less than three. That means your lipophilic efficiency needs to be greater than five. So this is a way of keeping track of how much lipophilicity you're adding during the chemistry process. And and trying to ensure that you're not adding to much. And you're getting potency for the right reasons, not the wrong reasons. The same is true of molecular weight. The same kind of convention has been developed. and, and, and the the basis for this came originally from a study that was published by Wenlock and coworkers back in 03. Where they showed that looking at a series of snapshots of approved drugs and drugs in various stages of clinical development. That if you look at, the average molecular weight of an approved drug, versus their snapshot of what was going on in, in clinical development, you could see that. What must be happening during the course of development is that on average, the smaller molecules we're going to, were having big greater success rate. So nature is clearly favoring smaller or less lipophilic molecules as you're as you're driving towards making a drug. And you can see that borne out in this histogram on the right, where you look at marketed oral drugs. Centroid is considerably lower molecular weight than the snapshot of the phase one compounds. So this metrical lean was developed minus the log of the ic50 and the measure of potency divided by the number of non hydrogen atoms and again the goal is to get the best bang for the buck as you make a chemical modification during the optimization process. So, again, examplar values, IC50 better than 10 nanomol, our molecular weight less than 400. That implies the LEAN's going to be better than 0.27. So we're no longer focused on potency. We're focused on potency at the right price in terms of both molecular weight and in terms of the lipophilocity lipophilocity of the small molecule. So the way we were using this at SGX and then subsequently Lilly was to actually plot lean versus LLE for compounds that were being synthesized for use against a particular target. And what you can see is that during the course of the optimization process you go. From the bottom left to the top right, and in so doing you get into this, the right zone, in terms of the the properties of the compound LE greater than five, the leading value greater than 0.27. The other thing you'll notice, is that you begin to see more of these green circles. Meaning the drugs have, the small molecules, the would be drugs, have got accepetable half-lives, when exposed to[UNKNOWN] microsomes. So not only are you getting something thats going to get through the the intestine, but you're also, and and is going to have a minimum we hope of off-target binding properties. But is also going to have the right level of metabolism as its as it passes through the liver in the particularly in the first part when it goes from the gut to the circulation. So these guidelines a were developed as part of a six signma pro project that I co led. with the, the top chemist at Lilly at the time when we were both there. we've since both left the company. where the goal is molecular weight less than 400, cLogP less than three and then these lean and LLE target values that I talked about and and the goal is just basically shoot an arrow at a bullseye. And, and be mindful of the fact that if you stray too far from the bullseye things things can deteriorate very rapidly. Something I haven't talked about is the fact that a one seems to do better if the small molecules are not flat actually have cairo centers have have sp3 carbons in them. As is the case with many natural products. We know many natural products have gone on to become drugs, or analogs thereof have become drugs. But, what we, what we also know is that natural products are very hard to work with. A challenge for medicinal chemists today is to make small molecule would be drugs that have more natural product-like properties. Not only are they going to be lower molecular weight, lower in their lipophilicity, but they're also going to be less planar, less flat, and have a better balance between nitrogen and oxygen. That's another feature of natural products that you don't see in in approved drugs.