How scientists discover new drugs against viruses: Medicinal Chemistry & Drug Design (Hepatitis C)

Let's explore drug design and medicinal chemistry by looking at GSK's development of Hepatitis C Virus inhibitors!

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Correction: Before the nerds call me out 🤓 - some visuals are missing the N-methyl group on the amide and aryl fluoride on the inhibitor

00:00 Drug discovery is not easy
02:30 What is Hepatitis C and why do we care
07:14 How to inhibit a virus
08:57 Chemical optimization & structure-activity relationship
13:22 UNEXPECTED turn of events in clinical development
18:44 Implications of new design on DMPK and clinical success

Key references:
- Design of N-Benzoxaborole Benzofuran GSK8175—Optimization of Human Pharmacokinetics Inspired by Metabolites of a Failed Clinical HCV Inhibitor: J. Med. Chem. 2019, 62, 7, 3254
- Discovery of a Potent Boronic Acid Derived Inhibitor of the HCV RNA-Dependent RNA Polymerase: J. Med. Chem. 2014, 57, 5, 1902
- HCV796: A Selective Nonstructural Protein 5B Polymerase Inhibitor with Potent Anti-Hepatitis C Virus Activity In Vitro, in Mice with Chimeric Human Livers,and in Humans Infected with Hepatitis C Virus: Hepatology 2009, 49, 3, 745

Some recommended books on organic synthesis:
- Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
- Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
- Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
- Nicolaou et al; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
- Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
- Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures)

[benmcreynolds]

I think chemistry and biology is the most facinating thing. It's literally like discovering cheat codes for Life. There is so many layers to the knowledge and outcome of different scientific discoveries. The natural world is facinating.

[mr.deonchemistry]

Excellent video. I was part of the medicinal chemistry team that discovered Daclatasvir at BMS.

[definetlynotacomment]

Another Banger! You surprised me again, I expected learning a little about pharmacokinetics. But the nuanced context of some of the inner workings of the pharmacological industry and by extension public health was unexpected, but very interesting.
Well almost as unexpected as boron.

[dalelane]

If it's not working, chuck a fluorine in there to tighten stuff up and pull evrything in tight. Never fails to amaze me the increase bioactivity that comes with a safely incorporated F.

[chadkline]

This guy is a legitimate genius. You're lucky to have access to his mind.

[some_guy___]

Very timely, my med chem exam is in a couple days. Learning about the design process was great revision and application of the course material :)

[fsen]

woah boron in a pharmaceutical, thats not something you see very often

[yxlop]

Another excellent video, offers some great insight into drug developement

[gmcenroe]

Great review, I worked at NIBR on antibiotics and antivirals.

[MultiMarionett]

Cool video, it was realy interesting to see the road and thouht process behind the development of a drug.

[ssj]

Just git my bachelor's in biochem plan to get my PhD in Organic Chem and focus on medicinal chem/Pharmacology

[ksa]

Hello, I greatly benefit from your videos; first and foremost, thank you for creating such high-quality content. I have a question: could you make a video explaining how molecules that act as anti-addiction agents, work?

[UrMom-qhre]

I’m only in my sophomore year of college taking Orgo 2, and yea, I was confused for about 90% of the video, but I am glad I understood some of it lol

[seanroark]

do they hide it's effectiveness and mischaracterize its purpose and effects so they can maintain an EUA?

[drasiella]

I was listening to your narrations and fell asleep with apple pie in the oven...

It baked for 2h but did not burn!

[_macrophage]

Great video and explanations. Gilead is pronounced with a G like Gate not with the J sound. Gill-EE-add

I had HCV and was treated/cured with Mavyret.

[ReLoadedProject]

I found this so interesting but this shit flew so far over my head. I wish I could understand it.

[.]

Memes are the only correct way to learn chemistry

[glebanful]

The ending is so sad. With all the time spent on optimization, some stupid unexpected effect killed it all.

[dyap]

Cool video and channel. Do you have any thoughts on pyrazole chemistry and applications in the pharmaceutical industry? I just found your channel and got to look over your other videos!