 So how do we create molecules that fulfill all the admin talks properties in general? It's hard, but there are a couple of rules of thumbs in particular one called Leipensky's Rule of five So the four rules in Leipensky's rule of five is not an oxymoron But this is not because there are five rules, but all these rules are multiples of five so the first thing Leipensky said these are merely observations of typical drugs that up until the 1990s or so had been successful It should the weight Should be below 500 Doltons So that's another way of saying that the molecular the weight of one molecule should be less than 500 grams per mole a 500 units Atomic units and that means because things that are too large will likely not be able to go through the blood brain barrier They might not go through membranes. The solubility might be bad, etc. It's just this is just a rule of thumb It's an order of magnitude in practice things that are too large just won't work to log P Should be less than five Yeah, that sounds completely Taken out of the blue it is taken out the blue So log P P is really the octanol to water partitioning Octanol to water and this means that it can't be too hydrophobic So if it's very very low that would mean that the quotient between octanol and water would be very low And that would mean that all the drug would like sorry it can't be too high If all the drug would like to go in the octanol Then that would be great It would be instantly be soluble in fat and everything But it would not be able to be taken up in the bloodstream, right? And if it's not going to be taken up in the bloodstream, it's never going to reach my brain and then we've lost So it can't be too hydrophobic. That's all it says here three there should be less than five Eight spawned Donors You know what the hydrogen bond donor is right, but I will write it anyway as an example and Four there should be less than ten eight spawned acceptors That would just be an O Both rule three and four refer to the fact that if there are too many hydrogen bond donors and acceptors This small molecule would be very hydrophilic and if it's very hydrophilic It's certainly going to be very soluble in the blood, which is good but then it will not be able to go through say the membrane and the particular the blood brain barrier and Most of the binding sites for these small drugs are also going to be small and hydrophobic So it can't be too hydrophilic and it can't be too hydrophobic It has to be just right in between and it can't be too large either Then I always started to restrict these drugs quite a lot There is a fifth rule that is not really a real Lepinsky rule, but I'll add that in a second But just to show you an example drug That fulfills these rules. Do you know what this is? This is that's a PAM. Do you know what that's a PAM is? Well, you probably haven't heard of it and that's because many of these drugs They have one chemical name which is the real the real scientific name we use for them But then drug design companies, pharma companies They want a fancy marketing name And this marketing name is frequently different in Europe versus the US partly because they want to be able to protect the name rights So That's a PAM that you've never heard of that is the molecule usually sold under the marketing name Valium So this is a strong sedative and everything It is successful. There are not too many side effects, but it's relatively easy to overdose on So it's it's certainly not a non dangerous drug That's a PAM is I forgot what the exact molecular weight is but it's relatively small So it certainly fulfills this one. It also fulfills log p again I don't remember exactly what it is. The point is that it fulfills it there is a three hydrogen bond acceptors and not a single hydrogen bond donor if I recall correctly So again, we're well within the range of these two limits, too Then there is something else here. That's very nice. There is only a single large bond that can rotate here And I'll add that as the fifth. Occasionally we we say This is not really an original Lipinski rule of five, but occasionally we say less than five freely rotating Bonds So why is it so bad to have freely rotating bonds? Well, that has to do with the free energy in exactly the same way that you learned from protein folding So if you were to have two molecules one that is very floppy and flexible, let's say with 10 freely rotating bonds here What's going to happen to the entropy of that molecule once you force it to actually go into a binding site? That's right You can have a gigantic reduction in entropy if the molecule was very free out of water If you have a gigantic reduction in entropy, that means that it's not going to be good for free energy at all It's likely not going to be an efficient binder But drugs with lots of these aromatic rings lots of things that are tied up here So it can't really rotate that much. It's already restricted out in water So when you're moving this molecule from the water to the binding site, there is not a gigantic reduction in entropy And that means that we will likely get a free better free energy of binding The other less noble part is that the more freely rotating bonds there are The harder it is for us to predict what the exact shape of it is So it's simply it's easier to work with molecules that are not as flexible, but that wasn't really Lipinski's rule Again, these are purely phenomenological. These are things that usually make used to make for good drugs So when how frequently is it that we get a new drug like this? Doesn't happen anymore. The problem is that at least when I looked at this a few years ago We hadn't had a new drug fulfilling all the Lipinski's rules of 5 since 1996 So this classical traditional drug design doesn't really work anymore There are either side effects or for whatever reason they never make it to the market So it's harder much harder to design drugs than we think a whole bunch of these traditional drugs say aspirin They would likely not Be approved on the market they appear today because there are side effects that 50 or 100 years ago We consider them acceptable by today's standards. They're not acceptable anymore And this is why drug design is so expensive most drugs tend to fail There are very few that make it all the way and the further along you are the riskier things get because you've invested so much money