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)

[@benmcreynolds8581]

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.

[@totalsynthesis]

Agreed!!

[@petrabraham9512]

100%

[@mr.deonchemistry4708]

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

[@totalsynthesis]

Thanks - and hats off! 👏

[@dalelane1948]

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.

[@totalsynthesis]

*F*acts 😎

[@definetlynotacomment1184]

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.

[@samueldeschwanden3065]

Best man, keep up the good work

[@alexandraschneider5651]

Amazing work as always!🔥🔥🔥🔥

[@UrMom-qh5re]

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

[@totalsynthesis]

Good job on the 10% 💪😂

[@chadkline4268]

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

[@yxlop4893]

Another excellent video, offers some great insight into drug developement

[@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 :)

[@totalsynthesis]

Good luck! 💪

[@MultiMarionett]

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

[@totalsynthesis]

Thanks! Will do more drugs in future

[@Numb40]

Excellent!

[@fsen1999]

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

[@fsen1999]

commented before i saw that exact response highlighted in the video lmao

[@totalsynthesis]

@@fsen1999 😂😂 got'em

[@seanroark6121]

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

[@ssj6000]

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

[@totalsynthesis]

Nice, good luck!

[@gmcenroe]

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

[@totalsynthesis]

Awesome

[@ksa4979]

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?

[@totalsynthesis]

Thank you!! Well there are many different mechanisms depending on the compound. I touch on some of them partially in other videos like the one on ibogaine. But I will keep it in mind for a general video perhaps!

[@Peator2]

what is the polar part of the inhibitor some stuff is not clear

[@dyap3925]

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!

[@totalsynthesis]

Thanks for watching!! Any reason why you are specifically interested in pyrazoles?

[@dyap3925]

@@totalsynthesisI'm an undergrad doing a research project on pnictogen chemistry, and coincidentally I'm using some pyrazole derivatives to make my ligands. (I'm actually applying for pharmacy school and it seems pretty lucky of me to stumble onto your channel lol)

[@oneweekyt1861]

awesome to hear

[@drasiella]

I was listening to your narrations and fell asleep with apple pie in the oven... It baked for 2h but did not burn!

[@totalsynthesis]

😅 I should start an ASMR channel

[@drasiella]

@@totalsynthesis thats never a bad idea. I enjoy falling asleep while listening about science I have no clue of.

[@VKHSD]

Yess i understand this completely

[@totalsynthesis]

😂

[@1.4142]

Memes are the only correct way to learn chemistry

[@ReLoadedProject]

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

[@knivesnico8775]

Hola I enjoy my low iq since i can laugh at keys dangling in front of me, endless entertainment

[@_iakvb771]

Based

[@_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.

[@totalsynthesis]

Thank you - and great to hear!

[@_macrophage]

@@totalsynthesis Keep these awesome videos coming

[@anonamemous6865]

Gilyad?

[@11thmileaim90]

When we expect hepatitis b cure?!

[@darcoln3208]

Got anything on PROTAC or targeted protein degradation (TPD) molecules?

[@totalsynthesis]

Really exciting field - will consider for future videos

[@darcoln3208]

@@totalsynthesis Awesome. Thanks.

[@11thmileaim90]

When we expect cure hepatitis b?

[@glebanful]

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

[@SacredQuack]

I work in MedChem. The Brainpower behind just one target is amazing but often after 10s of millions have been spend the target gets cancelled bcs. no molecule that is good enough has been found. And Drugs that are really profitable are also not as common in spite of the company spending billions of Dollars in to pharmaceutical research.

[@totalsynthesis]

Nice. Absolutely! And on the topic of profitability, funnily enough, sometimes simple "non-innovative" small molecules can drive billions in profit whereas more expensive agents (e.g., gene or cell therapies), commonly creating uproar in broader society upon hearing price points, do not even reach $1bn sales given low addressable patient pool. It definitely is a very complex but transformational field.

[@johndeaux8815]

The human remains at that Triangle Park place were the participants that would’ve made the study size a round number. For legal reasons this is a joke.

[@pinobear5313]

IQ 50 reporting in god bless everybody don't get cancer or hepatitis C god speed

[@utpalmukherjee7270]

Wow..I didn't get anything

[@boldsquid8940]

I am too dumb to understand.