Okay, so what do I mean by an Iterative Process. the previous speaker, he was talking about targets and, and, and what not. On the far right hand side of the screen here these are generally concepts, particularly in the small molecule chemists' minds, different options that they're going to explore when they start synthesizing new molecules. They're going to look at shapes of the molecules. Some may start with fragments of molecules to generate leads. Others will do virtual screening approaches, computational type applications. In other words, they'll have a database of information of different molecules in one, two, three dimensional images, and they'll look at which ones give them the best profile based on perhaps, the three dimensional fit and how it interacts with the target. others come up, where we use De Novo design, and all of these concepts are usually driven by the philosophy of that chemist. So, some believe more strongly in one approach over the other, OK. It's not to say that one is right and the others are wrong. It's just a blend of different approaches. let's see. Compound screening, so they all. So, so, coming out of these applications the chemist are going to generate molecules and they're going to enter the process. You got the designed elements, and then they're going to to introduce it against known ligands or cell assays that are specific to the target that they chose. OK. And if, if information is available, on the, the crystal structure of that protein, and that's what this co-crystal complexes are, it fits in the structure based drug design concept. If that information is available, the chemists will make use of it. it's an expensive process, and I'll go into a little bit more details on what that looks like but if that's available to this chemist they generally try to use that information to help design other molecules, and then they put it into, down below, in vitro, in vivo, metabolism, kinetic, all these other type of assays. So, until they get it right, what'll come out are some novel leads at the very bottom, okay. So that they might screen say, a couple of thousand, put it into the process, and it's a learning process right? And what will come out of the, the, very bottom, hopefully, will be molecules that they can push forward. Now, what this looks like from a, a tiered system, more like a, a funnel approach is, if we start from the top. there are going to be a series of assays and, and studies that the chemists and the biologists are going to have in mind. Now, I've got a list here. It's a blend of pharmacology, in vitro, in vivo type simple approaches, some in vitro drug metabolism applications. The one on the bottom, the mini ames, this is a genetic toxicology type assay. So the chemists and the biologists are going to look for quick signals just to give them a sense of, is that a thumbs up, or a thumbs down? Do they process the compounds and put it into the next tier of screen? So if we start in tier one, and process a thousand molecules through this tier one battery of studies, out from that thousand, may come about a hundred, and so then those hundred will enter a series of second tier studies, which will be more elaborate. OK. Maybe a little bit or some degree of similarity between the tier one type assays but more robust. OK. And out of the tier two studies they'll process those and they'll end up with maybe five that can go into further deeper type testing. OK? When this all comes together, a part of that, that tiering process, this is what it looks like. we start on the left, top left corner, you've got your target this is a, basically a molecule in the binding domain of the given target. Chemists do their thing, they, they generate the compounds that are introduced into the in vitro, pharmacology assays they're looking for a certain potency early on, say 100 nanomolar activity. Once it hits that or passes that gate, then it advances onto selectivity type assays. OK? I'll go a little bit more detail on the selectivity approach in a few slides in a few minutes. After the selectivity assays, then they'll put it through a series of other type assays. They pass through that, then it goes into some more robust in vivo assays. These are typically given by a parenteral route as well as an oral route. Even if a drug is intended to be given orally, we'll also test the molecule by the intravenous route, particularly in pharmacokinetic type application. OK? Once we have our golden babies, if you will, right, the premier molecules of everything that's gone through this process then we introduce it into a series of robust assays. These touch on drug safety profiling in animals, they touch on metabolism. HERG Channel study, this is a routine assay that came into a play about between 10 and 15 years ago as an absolute assay to check for cardiovascular liabilities. So, well before you guys were in, in the university setting, you guys were all little folks, there was a drug that, made it to the market, and they didn't do a thorough enough job, and there was a drug interaction that produced heart effects. The drug was instantly taken off of the market because it killed people, right? and it doesn't take very many patients, to remove the drug off of the market. And so as a result, it highlighted cardiovascular safety. And so some scientists came up with this Herg Channel assay, stands for Human Ether-Ă -go-go, Channel, OK. this is a simple ion channel type assay that we look and build in routinely. From the very early stages along the way for cardiovascular liability. So it, it gives us a nice signal again thumbs up or thumbs down. And then genetic toxicology. So, are you guys familiar with the word genetic toxicology, what it is, and, I know I'm going to be throwing out terms, and probably have already, that you may not be so familiar with. who in the audience knows what's meant by genetic toxicology? No one. I didn't think so. Oh, okay cool. What this refers to are any potential for genetic or DNA damage effects, OK. So there are standard batteries of tests that we incorporate. There's one that you may have heard of. It's called an Ames Assay. This is a bacterial assay. And we use some mammalian systems and some in vivo models that give us a nice cross section of the potential for genetic damage to a mammalian system. We don't want any of that, OK? So this is very important as part of the whole R&D process.
