WEBVTT 00:00:00.000 --> 00:00:02.399 Hey everyone, have you ever swallowed a pill 00:00:02.399 --> 00:00:05.639 and thought, how in the world did someone even 00:00:05.639 --> 00:00:08.820 figure out how to make this thing? I know I have. 00:00:08.939 --> 00:00:11.019 It really is incredible when you think about 00:00:11.019 --> 00:00:13.519 it. Yeah, so today we're gonna do a deep dive 00:00:13.519 --> 00:00:15.880 into this whole world of drug discovery. Sounds 00:00:15.880 --> 00:00:18.600 good to me. Specifically we're focusing on like 00:00:18.600 --> 00:00:21.570 those very first steps. You know, how do you 00:00:21.570 --> 00:00:24.230 go from a scientist having like an initial aha 00:00:24.230 --> 00:00:27.589 moment to that turning into an actual medicine 00:00:27.589 --> 00:00:29.949 that people can take? Right. It's a long road. 00:00:30.190 --> 00:00:32.869 Right. It is. So basically, imagine you've handed 00:00:32.869 --> 00:00:35.350 us like a stack of research papers, a bunch of 00:00:35.350 --> 00:00:37.869 notes. Yeah. Like how do new drugs actually get 00:00:37.869 --> 00:00:41.369 discovered? Our mission today is to take all 00:00:41.369 --> 00:00:43.869 that information and like boil it down to the 00:00:43.869 --> 00:00:46.570 most important, coolest stuff. Yeah. Try to make 00:00:46.570 --> 00:00:49.159 sense of it all. Exactly. And I think you're 00:00:49.159 --> 00:00:50.640 the perfect person to help us do that. I'll do 00:00:50.640 --> 00:00:53.600 my best. You eat, sleep, and breathe drug discovery. 00:00:53.820 --> 00:00:55.500 Well, most days at least. So you're going to 00:00:55.500 --> 00:00:57.439 break down the science for us, but also show 00:00:57.439 --> 00:01:00.500 us how amazingly complex it is. It definitely 00:01:00.500 --> 00:01:02.740 is. So are you ready to get started? Definitely. 00:01:02.799 --> 00:01:05.840 Let's go. OK, great. So first off, we need to 00:01:05.840 --> 00:01:08.700 wrap our heads around just how big of a deal 00:01:08.700 --> 00:01:10.599 this whole thing is. I mean, we're talking 10 00:01:10.599 --> 00:01:13.980 to 15 years. Oh, yeah. At least. And. billions, 00:01:14.400 --> 00:01:17.900 billions of dollars to take a drug from like 00:01:17.900 --> 00:01:21.939 a scientist bench in the lab to an actual medicine 00:01:21.939 --> 00:01:23.620 cabinet, right? It's a massive undertaking for 00:01:23.620 --> 00:01:25.900 sure. Massive. And, you know, our listeners have 00:01:25.900 --> 00:01:28.840 specifically asked us to like zoom in on those 00:01:28.840 --> 00:01:31.260 really early stages. OK, yeah, the early stages. 00:01:31.299 --> 00:01:33.739 That initial like spark of an idea where they 00:01:33.739 --> 00:01:36.340 find a molecule that they think might actually 00:01:36.340 --> 00:01:38.260 work as a medicine. And how do they even know 00:01:38.260 --> 00:01:40.980 where to start? So it all begins with something 00:01:40.980 --> 00:01:43.400 called high throughput screening. Right. Sounds 00:01:43.400 --> 00:01:45.159 kind of fancy, right? Yeah, it is a bit of a 00:01:45.159 --> 00:01:47.379 mouthful. It is. But basically, it's kind of 00:01:47.379 --> 00:01:51.439 like imagine a lab where robots are doing all 00:01:51.439 --> 00:01:56.060 the chemistry work. OK. And they're testing thousands, 00:01:56.219 --> 00:01:58.959 even millions of different compounds against 00:01:58.959 --> 00:02:01.120 like a specific disease targets. You can almost 00:02:01.120 --> 00:02:03.739 think of it like a giant chemistry lottery. Oh, 00:02:03.739 --> 00:02:06.019 I like that. That's a good way to put it. Yeah. 00:02:06.219 --> 00:02:08.039 OK, so that makes sense. But where do all these 00:02:08.039 --> 00:02:09.639 compounds even come from? It's not like they 00:02:09.639 --> 00:02:12.439 just magically appear. Yeah, not quite magic. 00:02:12.580 --> 00:02:14.300 But it's pretty cool where they come from. You 00:02:14.300 --> 00:02:17.039 have these huge libraries of chemicals that have 00:02:17.039 --> 00:02:19.539 been, you know, built up over the years. Some 00:02:19.539 --> 00:02:21.400 of them have been made in labs. Others, they 00:02:21.400 --> 00:02:24.120 come from natural sources like plants. Oh, interesting. 00:02:24.240 --> 00:02:26.780 And increasingly, scientists are actually using 00:02:26.780 --> 00:02:29.500 computers to just design new molecules from scratch. 00:02:29.580 --> 00:02:32.099 Wow. So, you know, it's really a cool mix of 00:02:32.099 --> 00:02:34.979 like old school chemistry and like super cutting 00:02:34.979 --> 00:02:38.000 edge tech all kind of coming together. OK. So 00:02:38.000 --> 00:02:40.259 you've got these robots. They're sifting through 00:02:40.259 --> 00:02:43.710 this giant library of chemicals. What are they 00:02:43.710 --> 00:02:46.490 actually looking for in this like molecular lottery? 00:02:47.169 --> 00:02:50.389 So they are looking for what we call a hit. A 00:02:50.389 --> 00:02:53.629 hit. Which is basically a compound that seems 00:02:53.629 --> 00:02:56.349 to do something to the disease target that we're 00:02:56.349 --> 00:02:58.930 interested in. Okay. So for example, let's say 00:02:58.930 --> 00:03:01.169 we're trying to make a new painkiller. Okay. 00:03:01.449 --> 00:03:04.689 A hit might be a compound that blocks a certain 00:03:04.689 --> 00:03:07.669 receptor that's involved in pain. But, and this 00:03:07.669 --> 00:03:10.370 is important, a hit is just the first step in 00:03:10.370 --> 00:03:13.610 a very, very long journey. So it's like finding 00:03:13.610 --> 00:03:16.430 a diamond in the rough, right? It has potential. 00:03:17.259 --> 00:03:20.360 but it still needs a lot of work before it becomes 00:03:20.360 --> 00:03:22.900 like that beautiful sparkly gem. That's a great 00:03:22.900 --> 00:03:24.900 analogy and that's where medicinal chemistry 00:03:24.900 --> 00:03:26.780 comes into the picture. Okay, so tell me more 00:03:26.780 --> 00:03:29.039 about that. So medicinal chemists, they are the 00:03:29.039 --> 00:03:32.000 master crafts people who take this promising 00:03:32.000 --> 00:03:35.180 hit compound. Okay. And they're carefully modifying 00:03:35.180 --> 00:03:38.039 it, tweaking it to try and turn it into something 00:03:38.039 --> 00:03:41.340 that's safe and effective as an actual medicine. 00:03:41.620 --> 00:03:44.900 Okay, so what are some of the challenges they 00:03:44.900 --> 00:03:47.830 run into? because it can't be as easy as it sounds, 00:03:47.969 --> 00:03:50.849 right? Oh, no, definitely not. So, for one thing, 00:03:50.930 --> 00:03:53.449 the het compound, it might be toxic, you know? 00:03:53.449 --> 00:03:55.370 It could break down too quickly in the body. 00:03:55.550 --> 00:03:58.669 It might not even get absorbed properly. Sometimes 00:03:58.669 --> 00:04:01.030 it could even interact in a bad way with other 00:04:01.030 --> 00:04:03.169 medicines that someone's taking. Oh, wow. So 00:04:03.169 --> 00:04:05.310 there's a ton of obstacles that they have to 00:04:05.310 --> 00:04:07.509 overcome. So it's kind of like a giant puzzle, 00:04:07.629 --> 00:04:10.129 right? You're tweaking this molecule, but each 00:04:10.129 --> 00:04:12.650 change could have some unintended consequence. 00:04:13.009 --> 00:04:15.250 Right, exactly. It's a really delicate balancing 00:04:15.250 --> 00:04:17.269 act. They have to boost the drug's effectiveness, 00:04:17.449 --> 00:04:19.269 but also make sure it doesn't cause a lot of 00:04:19.269 --> 00:04:21.810 side effects. And then also you have to make 00:04:21.810 --> 00:04:23.670 sure that it can be made into like a pill that 00:04:23.670 --> 00:04:26.209 someone can actually swallow or an injection 00:04:26.209 --> 00:04:28.910 or something. Right. Practical stuff. Exactly. 00:04:28.990 --> 00:04:31.120 It's not easy. So I'm curious, do you have any 00:04:31.120 --> 00:04:34.680 examples from your own work at OPR &D that can 00:04:34.680 --> 00:04:36.500 kind of bring this all to life? Like how does 00:04:36.500 --> 00:04:38.660 this actually work in the real world? Oh yeah, 00:04:38.860 --> 00:04:41.000 definitely. Let me tell you about this one project 00:04:41.000 --> 00:04:44.379 we were working on. It was a potential new treatment 00:04:44.379 --> 00:04:47.319 for Alzheimer's disease. Oh, wow. OK. And we 00:04:47.319 --> 00:04:50.560 had found this hit compound that seemed really 00:04:50.560 --> 00:04:53.279 promising. It showed really good activity against 00:04:53.279 --> 00:04:56.000 one of the key enzymes that we think drives the 00:04:56.000 --> 00:04:58.360 disease. That's amazing. So you guys had this 00:04:58.360 --> 00:05:00.759 potential breakthrough on your hands. What happened 00:05:00.759 --> 00:05:03.279 next? Well, unfortunately, we ran into a big 00:05:03.279 --> 00:05:05.860 problem pretty quickly. The tests showed that 00:05:05.860 --> 00:05:08.360 the compound was being metabolized super fast 00:05:08.360 --> 00:05:11.560 in the liver. So it was basically getting broken 00:05:11.560 --> 00:05:13.660 down by the body before it could even reach its 00:05:13.660 --> 00:05:15.920 target in the brain. Oh, that's gotta be so frustrating. 00:05:16.079 --> 00:05:18.899 It's like the compound got lost on its way to 00:05:18.899 --> 00:05:21.220 fight the disease. Yeah, exactly. So what did 00:05:21.220 --> 00:05:24.240 you guys do? Well, it was a setback for sure, 00:05:24.600 --> 00:05:27.759 but it's actually pretty common in drug discovery. 00:05:28.300 --> 00:05:31.259 So we all put on our medicinal chemistry hats 00:05:31.259 --> 00:05:33.920 and we started brainstorming, like how can we 00:05:33.920 --> 00:05:36.439 tweak the structure of this molecule to make 00:05:36.439 --> 00:05:39.180 it more resistant to metabolism? Okay, how do 00:05:39.180 --> 00:05:41.240 you even go about doing that? Do you just like 00:05:41.240 --> 00:05:43.060 randomly start changing things until something 00:05:43.060 --> 00:05:46.670 works? Ha, no, I wish it was that easy. It's 00:05:46.670 --> 00:05:49.110 actually very systematic. So we used computer 00:05:49.110 --> 00:05:52.089 modeling to try and predict how different modifications 00:05:52.089 --> 00:05:54.009 would affect the properties of the molecule. 00:05:54.089 --> 00:05:57.029 Oh, cool. And then based on that, we synthesized 00:05:57.029 --> 00:05:59.089 a bunch of different versions of the compound, 00:05:59.550 --> 00:06:01.329 each one with just like a tiny little change 00:06:01.329 --> 00:06:03.250 to the structure. OK. And then we tested all 00:06:03.250 --> 00:06:05.290 those in the lab. So it's like being a molecular 00:06:05.290 --> 00:06:08.129 architect, right? Yeah. You're carefully redesigning 00:06:08.129 --> 00:06:10.550 the building blocks of this compound. Yeah, exactly. 00:06:10.689 --> 00:06:13.000 To get what you want. It took a lot of tries, 00:06:13.160 --> 00:06:16.199 but finally, after a ton of rounds of designing, 00:06:16.699 --> 00:06:19.139 making these new compounds and testing them, 00:06:19.480 --> 00:06:21.839 we finally found one that was much more stable 00:06:21.839 --> 00:06:25.379 in the body. That's amazing. Yeah. And the best 00:06:25.379 --> 00:06:28.420 part was it still kept its activity against that 00:06:28.420 --> 00:06:32.160 target enzyme that we wanted to hit. So you outmaneuvered 00:06:32.160 --> 00:06:34.819 the liver. You outsmarted it. I guess you could 00:06:34.819 --> 00:06:37.339 say that. It was a big win for the team, for 00:06:37.339 --> 00:06:40.029 sure. I bet. But of course, that was just one 00:06:40.029 --> 00:06:42.370 of many hurdles to get over. There's a ton more 00:06:42.370 --> 00:06:44.490 challenges to tackle before this compound could 00:06:44.490 --> 00:06:47.529 actually move on to the next steps and eventually 00:06:47.529 --> 00:06:49.629 become a medicine. Right. But this is a really 00:06:49.629 --> 00:06:51.889 good illustration of how important medicinal 00:06:51.889 --> 00:06:54.589 chemistry is. You're taking this promising hit 00:06:54.589 --> 00:06:56.470 and turning it into something that could actually 00:06:56.470 --> 00:06:59.350 be a drug someday. Exactly. It's a challenging 00:06:59.350 --> 00:07:01.750 field, but it's so rewarding to be a part of. 00:07:02.600 --> 00:07:05.420 You mentioned stability. What are some of the 00:07:05.420 --> 00:07:07.620 other things that medicinal chemists have to 00:07:07.620 --> 00:07:09.720 think about when they're refining these HIC compounds? 00:07:10.079 --> 00:07:13.120 So another big one is solubility. The drug, you 00:07:13.120 --> 00:07:16.139 know, it needs to dissolve properly in the fluids 00:07:16.139 --> 00:07:18.220 in your body so it can get absorbed and actually 00:07:18.220 --> 00:07:20.759 reach its target. Right. Makes sense. It's like 00:07:20.759 --> 00:07:23.319 when you dissolve sugar in water. Some things 00:07:23.319 --> 00:07:25.939 dissolve easier than others. Exactly. And if 00:07:25.939 --> 00:07:28.019 a drug doesn't dissolve well, then it's not going 00:07:28.019 --> 00:07:30.079 to get absorbed very well, which means it's not 00:07:30.079 --> 00:07:32.680 going to be as effective. So medicinal chemists, 00:07:32.680 --> 00:07:35.720 they spend a lot of time trying to improve the 00:07:35.720 --> 00:07:38.160 solubility of a compound. Sometimes they tweak 00:07:38.160 --> 00:07:40.740 its structure. Other times, they explore different 00:07:40.740 --> 00:07:43.680 what we call formulations. Formulations. What 00:07:43.680 --> 00:07:45.600 does that mean? So that's basically how the drug 00:07:45.600 --> 00:07:50.279 is packaged. Like, is it a pill? a capsule, a 00:07:50.279 --> 00:07:52.819 liquid, all those things can affect how it dissolves 00:07:52.819 --> 00:07:54.879 and gets absorbed in the body. Oh, interesting. 00:07:55.180 --> 00:07:58.259 So it's not just about the molecule itself. It's 00:07:58.259 --> 00:08:00.420 also about how it's given to people, how it's 00:08:00.420 --> 00:08:03.519 presented to the body. Exactly. It's a multifaceted 00:08:03.519 --> 00:08:06.660 problem. And medicinal chemists, they play a 00:08:06.660 --> 00:08:09.759 huge role in optimizing all those different aspects. 00:08:09.839 --> 00:08:12.660 So it's like chemistry, biology, and a little 00:08:12.660 --> 00:08:14.600 bit of like pharmaceutical engineering all rolled 00:08:14.600 --> 00:08:17.800 into one. Exactly. You have to have a deep understanding 00:08:17.800 --> 00:08:20.420 of how all these different pieces fit together. 00:08:20.959 --> 00:08:23.540 You know how molecules behave in different biological 00:08:23.540 --> 00:08:26.379 systems. It's fascinating. I can imagine. So 00:08:26.379 --> 00:08:29.149 we've talked about robots and libraries of chemicals, 00:08:29.569 --> 00:08:31.689 and then these really talented medicinal chemists 00:08:31.689 --> 00:08:34.250 who are like tweaking and refining those molecules. 00:08:34.690 --> 00:08:36.590 It's amazing to think about how much science 00:08:36.590 --> 00:08:39.419 and creativity goes into just those. first few 00:08:39.419 --> 00:08:41.519 steps of discovering a new drug. Yeah, it really 00:08:41.519 --> 00:08:43.259 does lay the groundwork for everything else that 00:08:43.259 --> 00:08:45.240 happens after. And I think it helps to explain 00:08:45.240 --> 00:08:47.980 why it takes so long and costs so much to make 00:08:47.980 --> 00:08:50.460 a new medicine. Right. Every single step is important. 00:08:50.899 --> 00:08:53.259 From finding that initial hit to optimizing all 00:08:53.259 --> 00:08:55.659 the different properties, it all matters. So 00:08:55.659 --> 00:08:57.960 at the end of the day, what are the key takeaways 00:08:57.960 --> 00:09:00.200 that you want our listeners to walk away with? 00:09:00.500 --> 00:09:02.980 What should they really remember about this early 00:09:02.980 --> 00:09:05.549 phase of drug discovery? Well, I think the first 00:09:05.549 --> 00:09:07.950 thing is to remember that drug discovery is not 00:09:07.950 --> 00:09:11.500 a straight line. You know, there's constant setbacks 00:09:11.500 --> 00:09:13.919 and unexpected hurdles. There's a lot of trial 00:09:13.919 --> 00:09:16.480 and error involved. Like navigating a maze. Right. 00:09:16.659 --> 00:09:19.320 Every turn could lead to a dead end or new path 00:09:19.320 --> 00:09:22.000 forward. Exactly. And the second thing is to 00:09:22.000 --> 00:09:24.200 remember that it's not just about finding a molecule 00:09:24.200 --> 00:09:27.059 that works against a disease target. Right. It's 00:09:27.059 --> 00:09:29.200 about making sure that molecule can actually 00:09:29.200 --> 00:09:31.840 become a medicine. You know, it has to be safe. 00:09:32.080 --> 00:09:33.740 It has to be effective. And you have to be able 00:09:33.740 --> 00:09:36.080 to actually give it to people. Right. So it has 00:09:36.080 --> 00:09:38.960 to survive the journey through the body. actually 00:09:38.960 --> 00:09:42.679 get to its target and then, you know, do its 00:09:42.679 --> 00:09:44.899 job without causing a bunch of side effects. 00:09:45.139 --> 00:09:47.440 Exactly. And that's where the expertise of those 00:09:47.440 --> 00:09:49.379 medicinal chemists comes in. Right. They're the 00:09:49.379 --> 00:09:51.500 ones that figure all that out. They're the unsung 00:09:51.500 --> 00:09:54.559 heroes. They use their knowledge of chemistry 00:09:54.559 --> 00:09:57.519 and biology to overcome all these challenges 00:09:57.519 --> 00:10:01.639 and actually turn these promising hits into real 00:10:01.639 --> 00:10:04.240 drug candidates. It's like taking a raw ingredient 00:10:04.240 --> 00:10:06.679 and turning it into this delicious gourmet meal. 00:10:06.840 --> 00:10:09.159 I like that. That's a great way to put it. So 00:10:09.159 --> 00:10:11.179 last but not least, what else should people remember? 00:10:11.480 --> 00:10:14.759 I think it's important to appreciate how collaborative 00:10:14.759 --> 00:10:18.120 drug discovery really is. Okay. You know, it 00:10:18.120 --> 00:10:20.320 takes scientists from all these different fields 00:10:20.320 --> 00:10:23.179 working together to solve these really complex 00:10:23.179 --> 00:10:25.879 problems. Yeah, like a team effort. Totally. 00:10:26.220 --> 00:10:28.740 It really is a testament to human ingenuity. 00:10:28.799 --> 00:10:31.779 Absolutely. And our drive to find better treatments 00:10:31.779 --> 00:10:34.539 for diseases. Well, I have to say, this has been 00:10:34.539 --> 00:10:37.159 so insightful. It's really cool to kind of get 00:10:37.159 --> 00:10:39.539 this peek behind the curtain and see how all 00:10:39.539 --> 00:10:42.679 these early steps in drug discovery really set 00:10:42.679 --> 00:10:46.480 the stage for future breakthroughs in medicine. 00:10:46.840 --> 00:10:49.039 I'm glad you enjoyed it. It's a field that often 00:10:49.039 --> 00:10:51.700 goes unnoticed, but it's really the foundation 00:10:51.700 --> 00:10:54.320 of everything we do in modern medicine. I agree. 00:10:54.669 --> 00:10:56.509 Well, thanks for joining us on this deep dive 00:10:56.509 --> 00:10:58.570 into the world of drug discovery. My pleasure. 00:10:58.909 --> 00:11:00.669 Hopefully you learned something new and exciting 00:11:00.669 --> 00:11:04.129 today. I hope so too. And until next time, keep 00:11:04.129 --> 00:11:06.250 those brains buzzing. We'll catch you on our 00:11:06.250 --> 00:11:08.990 next deep dive. See you then. Oh, yeah. Definitely. 00:11:09.750 --> 00:11:11.929 There's this one project that really stands out. 00:11:11.970 --> 00:11:14.730 It was a potential new treatment for Alzheimer's 00:11:14.730 --> 00:11:17.830 disease. Oh, wow. And we had found this hit compound 00:11:17.830 --> 00:11:20.250 that looked really, really promising. It had 00:11:20.250 --> 00:11:22.809 really good activity against a key enzyme that 00:11:22.809 --> 00:11:25.610 we think is involved in the disease. That's incredible. 00:11:25.889 --> 00:11:27.870 So you had like this potential breakthrough on 00:11:27.870 --> 00:11:31.169 your hands. What happened next? Well, the initial 00:11:31.169 --> 00:11:35.090 tests, they revealed a pretty major problem. 00:11:36.060 --> 00:11:39.000 the compound was being metabolized super fast 00:11:39.000 --> 00:11:41.679 in the liver, like really fast. So basically 00:11:41.679 --> 00:11:43.720 it was getting chewed up by the body before it 00:11:43.720 --> 00:11:45.440 could even get to the brain where it needed to 00:11:45.440 --> 00:11:47.399 be. Oh, that's such a huge setback. It's like 00:11:47.399 --> 00:11:50.100 the compound was getting lost on its way to the 00:11:50.100 --> 00:11:52.200 battlefield. Yeah, exactly. It was really frustrating. 00:11:52.820 --> 00:11:54.559 But you know, it's actually a pretty common challenge 00:11:54.559 --> 00:11:57.220 in drug discovery. Right. So. You know, what 00:11:57.220 --> 00:11:59.299 do we do? We gotta put on our medicinal chemistry 00:11:59.299 --> 00:12:02.299 hats and figure out how to fix it. So we started 00:12:02.299 --> 00:12:04.899 exploring ways to tweak the compound's structure 00:12:04.899 --> 00:12:07.460 to make it harder for the liver to break it down 00:12:07.460 --> 00:12:10.279 so quickly. Okay, how do you even do that? I 00:12:10.279 --> 00:12:12.799 mean, do you start changing things randomly until 00:12:12.799 --> 00:12:15.419 something works? No, I wish it were that easy. 00:12:15.559 --> 00:12:18.480 It's actually a really systematic process. So 00:12:18.480 --> 00:12:22.620 we used computer modeling to predict how different 00:12:22.620 --> 00:12:24.860 modifications would affect the molecule. Oh, 00:12:24.919 --> 00:12:26.980 cool. And then we synthesized a bunch of different 00:12:26.980 --> 00:12:29.360 versions of the compound, like each one with 00:12:29.360 --> 00:12:31.720 just a tiny little change to the structure. OK. 00:12:32.000 --> 00:12:34.299 And we tested each one in the lab to see how 00:12:34.299 --> 00:12:36.720 they behaved. So it's like you're a molecular 00:12:36.720 --> 00:12:39.779 architect, right? You're carefully redesigning 00:12:39.779 --> 00:12:42.000 the building blocks of the compound. Yeah, that's 00:12:42.000 --> 00:12:43.779 a great way to think about it. To make it do 00:12:43.779 --> 00:12:45.720 what you want it to do. Exactly. And you know 00:12:45.720 --> 00:12:48.960 what? It took a lot of tries, but we finally 00:12:48.960 --> 00:12:52.019 found one that worked. Oh, wow. Yeah, after tons 00:12:52.019 --> 00:12:54.480 of rounds of design and synthesis and testing, 00:12:55.039 --> 00:12:57.759 we finally landed on an analog that was way more 00:12:57.759 --> 00:12:59.860 stable in the body. That's amazing. And the best 00:12:59.860 --> 00:13:02.740 part? It still had great activity against that 00:13:02.740 --> 00:13:05.399 target enzyme. So you basically outmaneuvered 00:13:05.399 --> 00:13:07.919 the liver. You outsmarted it. I guess you could 00:13:07.919 --> 00:13:10.340 say that. Yeah. It was a huge win for the team. 00:13:10.559 --> 00:13:12.840 But of course, that was just one hurdle down. 00:13:12.960 --> 00:13:15.759 There's always more challenges to face before 00:13:15.759 --> 00:13:19.000 this compound could actually move on to the later 00:13:19.000 --> 00:13:21.259 stages of development. Right, of course. But 00:13:21.259 --> 00:13:24.019 it's a great example of how crucial medicinal 00:13:24.019 --> 00:13:26.700 chemistry is. You're taking this promising hit 00:13:26.700 --> 00:13:29.159 and turning it into something that could actually 00:13:29.159 --> 00:13:32.019 become a real drug someday. Yeah, exactly. It's 00:13:32.019 --> 00:13:34.480 a challenging field, but it's also incredibly 00:13:34.480 --> 00:13:37.620 rewarding. So we've talked about stability. What 00:13:37.620 --> 00:13:39.759 are some of the other properties that medicinal 00:13:39.759 --> 00:13:41.820 chemists need to consider when they're trying 00:13:41.820 --> 00:13:44.539 to refine these hit compounds? Another really 00:13:44.539 --> 00:13:47.159 big one is solubility. You know, the drug needs 00:13:47.159 --> 00:13:49.379 to be able to dissolve properly in the body's 00:13:49.379 --> 00:13:51.639 fluids. Okay. So it can be absorbed and reach 00:13:51.639 --> 00:13:54.440 its target. Right. That makes sense. It's kind 00:13:54.440 --> 00:13:56.440 of like when you try to dissolve sugar and water. 00:13:56.840 --> 00:13:58.639 Some things dissolve more easily than others. 00:13:58.860 --> 00:14:00.940 Exactly. And if a drug doesn't dissolve well, 00:14:00.980 --> 00:14:02.500 it's not going to be absorbed as efficiently. 00:14:02.500 --> 00:14:04.820 And that means it won't be as effective. Got 00:14:04.820 --> 00:14:07.639 it. So how do you improve solubility? Well, medicinal 00:14:07.639 --> 00:14:09.519 chemists can sometimes tweak the structure of 00:14:09.519 --> 00:14:12.200 the compound to make it more soluble. Or they 00:14:12.200 --> 00:14:14.639 can explore different formulations. Formulations. 00:14:14.879 --> 00:14:16.500 What's that? Oh, it's basically how the drug 00:14:16.500 --> 00:14:19.320 is packaged. You know, like, is it a pill? Is 00:14:19.320 --> 00:14:22.000 it a capsule? Is it a liquid? All of those things 00:14:22.000 --> 00:14:25.200 can affect how the drug dissolves and gets absorbed 00:14:25.200 --> 00:14:27.080 in the body. Oh, that's interesting. So it's 00:14:27.080 --> 00:14:29.659 not just about the molecule itself. It's also 00:14:29.659 --> 00:14:31.480 about how it's delivered to the body. Exactly. 00:14:31.639 --> 00:14:34.679 It's a really multifaceted challenge. And medicinal 00:14:34.679 --> 00:14:38.360 chemists play a huge role in optimizing all those 00:14:38.360 --> 00:14:40.259 different aspects. Wow. So it's like chemistry, 00:14:40.360 --> 00:14:43.019 biology, and a bit of pharmaceutical engineering 00:14:43.019 --> 00:14:45.480 all rolled into one. You got it. It's all connected. 00:14:45.840 --> 00:14:47.580 You have to understand how all these different 00:14:47.580 --> 00:14:49.600 pieces fit together, how the molecules behave 00:14:49.600 --> 00:14:51.360 in different systems. It's really fascinating. 00:14:51.480 --> 00:14:53.399 This has been amazing. I feel like we've gone 00:14:53.399 --> 00:14:56.259 from like robots in these huge libraries of chemicals 00:14:56.259 --> 00:14:58.700 to like the super detailed work of these medicinal 00:14:58.700 --> 00:15:00.679 chemists who are like carefully correcting these 00:15:00.679 --> 00:15:03.059 molecules. Yeah, it's been quite a journey. It 00:15:03.059 --> 00:15:05.279 really has. And it's so cool to see just how 00:15:05.279 --> 00:15:08.299 much like science and creativity goes into just 00:15:08.299 --> 00:15:11.220 those first few steps of you know, trying to 00:15:11.220 --> 00:15:13.460 discover a new drug. It really does lay the foundation 00:15:13.460 --> 00:15:15.679 for everything that comes after. Yeah, and it 00:15:15.679 --> 00:15:17.580 helps explain why it takes so long and costs 00:15:17.580 --> 00:15:20.500 so much money to develop a new drug. Yeah. Right, 00:15:20.539 --> 00:15:22.799 because every single step from finding that first 00:15:22.799 --> 00:15:24.679 fit to making sure that I have all the right 00:15:24.679 --> 00:15:27.600 properties, it all matters. Absolutely. Every 00:15:27.600 --> 00:15:30.379 step is critical to making sure that we end up 00:15:30.379 --> 00:15:32.480 with a safe and effective medicine for patients. 00:15:32.899 --> 00:15:34.820 So at the end of the day, what are the key takeaways 00:15:34.820 --> 00:15:37.940 that you want our listeners to walk away with? 00:15:38.330 --> 00:15:41.330 What should they remember about this early phase 00:15:41.330 --> 00:15:43.570 of drug discovery? Well, I think the most important 00:15:43.570 --> 00:15:46.629 thing to remember is that drug discovery is not 00:15:46.629 --> 00:15:49.250 a straight line. You know, there are always setbacks, 00:15:49.570 --> 00:15:51.889 unexpected hurdles, lots of trial and error. 00:15:52.009 --> 00:15:54.529 It's a really iterative process. It's like navigating 00:15:54.529 --> 00:15:57.419 a maze. Every turn could lead you to a dead end 00:15:57.419 --> 00:16:00.039 or like a new path forward. Exactly. And the 00:16:00.039 --> 00:16:02.039 second thing to remember is that it's not just 00:16:02.039 --> 00:16:04.559 about finding a molecule that works against a 00:16:04.559 --> 00:16:07.059 disease target. It's about making sure that all 00:16:07.059 --> 00:16:09.200 a cure can actually be turned into a medicine 00:16:09.200 --> 00:16:12.279 that is safe and effective and practical to give 00:16:12.279 --> 00:16:15.000 to people. Right. So it has to survive the journey 00:16:15.000 --> 00:16:18.259 through the body, actually reach its target and 00:16:18.259 --> 00:16:21.080 do its job. without causing a bunch of side effects. 00:16:21.620 --> 00:16:24.240 Exactly. And that's where the expertise of those 00:16:24.240 --> 00:16:26.940 medicinal chemists is so essential. They're the 00:16:26.940 --> 00:16:28.940 ones who figure all that out. Yeah, they really 00:16:28.940 --> 00:16:31.139 are like the unsung heroes of drug discovery. 00:16:31.200 --> 00:16:33.899 Absolutely. They use their knowledge of chemistry 00:16:33.899 --> 00:16:36.080 and biology to overcome all those challenges 00:16:36.080 --> 00:16:38.820 and turn those promising hits into actual drug 00:16:38.820 --> 00:16:40.799 candidates that can be tested and potentially 00:16:40.799 --> 00:16:43.419 move forward. It's like taking a raw ingredient 00:16:43.419 --> 00:16:45.399 and turning it into like a delicious gourmet 00:16:45.399 --> 00:16:48.120 meal. That's a great analogy. And last but not 00:16:48.120 --> 00:16:49.639 least, is there anything else that's important 00:16:49.639 --> 00:16:51.659 for people to remember? Oh, I think it's also 00:16:51.659 --> 00:16:53.720 important to appreciate how collaborative drug 00:16:53.720 --> 00:16:56.899 discovery is. It takes scientists from all these 00:16:56.899 --> 00:16:58.960 different fields working together to solve these 00:16:58.960 --> 00:17:01.620 really complex problems. Yeah, it's a real team 00:17:01.620 --> 00:17:03.779 effort. It really is. It's a testament to human 00:17:03.779 --> 00:17:07.259 ingenuity and our desire to find better treatments 00:17:07.259 --> 00:17:09.839 for diseases. I completely agree. Well, this 00:17:09.839 --> 00:17:12.579 has been so insightful. I feel like we've really 00:17:12.579 --> 00:17:15.200 gotten a glimpse into this world of drug discovery. 00:17:15.079 --> 00:17:18.160 and how those early steps are so crucial for 00:17:18.160 --> 00:17:20.240 medical breakthroughs. I'm glad you found it 00:17:20.240 --> 00:17:22.940 interesting. It's a field that often goes unnoticed, 00:17:23.079 --> 00:17:25.079 but it really is at the heart of modern medicine. 00:17:25.440 --> 00:17:27.099 Well, thanks again for joining us on this deep 00:17:27.099 --> 00:17:29.160 dive into drug discovery. We hope you learned 00:17:29.160 --> 00:17:31.779 something new and exciting today. And until next 00:17:31.779 --> 00:17:34.380 time, keep those brains buzzing. See you next 00:17:34.380 --> 00:17:36.799 time. We'll catch you on our next deep dive.