Jensen Huang’s comments from JPM24 are now summarized in a Nvidia blog post. He doubles down on exactly the kinds of things that I’ve been cautioning are wildly optimistic. More below. 👇🏽 1/ Usual disclaimer: it’s op-ed time again. My opinions alone, not my employer’s or anyone else’s. 1.5/

Time for another pharmacology tweetorial on another layer of the selectivity problem: drug promiscuity. Both the things we can control, and the things that are out of our hands thanks to good ol’ Mother Nature. 1/ Usual disclaimer: all thoughts and opinions in this post are my own, and don’t necessarily reflect the opinions of my employer. This thread will feature a higher proportion of opinion than normal, but with reasoning supplied. 2/

Time for another pharmacology tweetorial (X-torial?), this time on the subject of receptor occupancy and how it relates to selectivity. 1/ Usual disclaimer: all of this thread is my own thoughts and opinions on the subject, and does not necessarily reflect the views of my employer. Your mileage may vary. Some restrictions may apply. 2/

Continuing the occasional Friday pharma #EarlyCareer series. Last time we talked about site interviews. This time let’s talk about negotiating job offers. (Next time we’ll deal with the inevitable rejections.) 🧵 1/ Usual disclaimer: everything in this thread is my observations based on 20+ years of personal experience at pharmas big and small, and should not be construed as reflecting the opinions and practices of, nor an endorsement by, my employer. 1.5/

Continuing the Friday pharma industry #EarlyCareer tip series. Last time we talked about phone interviews. This time let’s talk about the next step, a really big one: on-site interviews. 🧵 1/ If your phone interview goes well, the hiring manager will usually invite you for a site interview. Pre-pandemic, that almost always meant traveling to the pharma R&D site for the interview. These days, it may also be done virtually on Zoom or Teams instead. 2/

Since we’re all watching The Last of Us, is it really true that we have nothing (other than bombs) for the coming fungal pandemic? Time to review what we’ve got in the pharmacopeia for fungal infections. Lest we all turn into zombies. 🧵 1/ Broadly, antifungals are woefully under-researched, even among anti-infectives. Fungi are more similar to animals than plants or bacteria. That relative same-ness means finding drugs that target fungi without targeting ourselves is tough. And resistance is ever on the rise. 2/

I’m going to offer some more regular industry #EarlyCareer tips on Fridays. Keeping this focused on chemistry in pharma since that’s what I know about.

Let’s start with applying for the job! 🧵 👇 1/ First off, unlike many other lines of industry work, in pharma chemistry we usually ask for a comprehensive academic-style curriculum vitae (CV) rather than a shorter résumé. Sometimes these terms get used interchangeably in the US, but they’re not the same. 2/

Time for a pharmacology tweetorial (of sorts) on one-eyed sheep. It’s an odyssey that began on Idaho ranches in the 1950s and ended over half a century later with the approval of several new cancer drugs for basal cell carcinoma and AML. 1/ Usual disclaimer: all opinions expressed herein are my own, and do not necessarily reflect the opinions of my employer. Nor am I a medical doctor slinging any medical advice. Any errors or omissions are because I’m just a simple chemist. 2/

By request, here’s a thread of threads rolling up all of the Drug Discovery Axioms. Bookmark for your convenience. May add a few more in the future. Axiom 1

https://twitter.com/KRHornberger/status/1592489494439395330

A few weeks ago, I was asked what kinds of questions I consider for career self-reflection — a process I recommend doing at least once a year. Below is a non-exhaustive set of questions. Feel free to add more reflection questions that have helped you in the comments! 1/11 1. Am I happy — at work, at home, and in between? A high-level question that allows for further introspection into root cause.
2. How financially secure am I in my current role? Does it pay the bills, but also allow retirement & college savings, funding vacations, etc.? 2/11

Time for another pharmacology tweetorial, this time a second installment on structural alerts. We’ll cover more things about anilines and phenols beyond redox cycling. We’ll also talk about glucuronides generally and a reactive subset (acyl glucuronides) specifically. 1/ For a refresher, please first take a gander at this first thread on structural alerts, where I talked in depth about redox cycling. A lot of these concepts will reappear and be further elaborated upon here. 2/

https://twitter.com/KRHornberger/status/1485948686412746762

More about “leaving academia”. Even the language of “leaving” is biased and implies that: 1) if there were just more academic jobs, then *of course* everyone would stay; 2) academia is the pinnacle job. None of this is true. 1/7 Most PhDs will pursue non-academic careers. That’s the default state.

Certain folks in academia: (sotto voce) Well, obviously the *best* ones are the ones who stay.

Everyone else: You know it’s just because there’s more jobs available in other employment sectors, right?

2/7

Time for another pharmacology tweetorial, this time on structural alerts (part 1: redox cyclers) – or broadly speaking, why medicinal chemists don’t like to work with certain functional groups if they can help it. 1/ Usual Disclaimer: this thread represents my own views and opinions, not necessarily those of my employer. 1.5/

Time for another pharmacology tweetorial, this time on irreversible inhibitors, their biochemical characterization, and their chemical optimization. 1/ References first. There are lots of papers and reviews on this topic, but a cogent and relevant one is this one by Strelow. Not the only articulation of k_inact/KI ratios out there, but it’s a really good one. 2/
journals.sagepub.com/doi/full/10.11…

Time for another pharmacology tweetorial, this time about the distinction between clearance and intrinsic clearance. And also a cautionary tale about how we’re so often misled by over-focus on the former. 1/ References first. A key one for this discussion is this 1977 paper from Pang and Rowland, which describes the well-stirred model of clearance in considerable detail. (Not the first paper on the model, but maybe the most thorough.) 2/
link.springer.com/article/10.100…

Time for another pharmacology tweetorial, this time on the distinction between IC50 and Ki. 1/ References first. There’s really one that’s central for this discussion, this seminal 1973 masterwork from Cheng and Prusoff. 2/
sciencedirect.com/science/articl…

The molnupiravir discussion last week revealed to me a woeful gap in my nucleoside prodrug knowledge. Spurred on by @GusTheChemist, I've been working to close that gap.

Never be ashamed to admit when you don't know something. These are the best opportunities to learn! 1/4 Gus got my reading rolling with this review on phosphate and phosphonate prodrugs. Putting that first phosphate on in vivo is slow, so having it already present is a strategy. 2/4
pubs.acs.org/doi/10.1021/cr…

🧵 I won’t wade too far into the debate du jour re: the Nobel and Hajos (who is alive), Parrish, Eder, Sauer, and Wiechert. But maybe a slight aside on the Hajos-Parrish ketone and its slightly larger cousin, the Wieland-Miescher ketone. 1/ The Hajos-Parrish and Wieland-Miescher ketones have had a big impact on steroid synthesis. They’re still central to teaching organic synthesis in the first year of grad school (AFAIK). 2/
en.wikipedia.org/wiki/Wieland%E…

Time for another PK tweetorial, this time featuring a deeper dive on the not-so-mystical art of human dose prediction. 1/ I’ve argued previously that human dose is the master optimization parameter in medicinal chemistry. Like death, it can’t be cheated. All variables come together in this one number. 2/

🧵By request, here we go with another PK tweetorial, this time on the free drug hypothesis. 1/ References up front. A great one on how to properly use plasma protein binding (PPB) to interpret PD/efficacy data and NOT use PPB as an optimization parameter. This paper is a true classic. I’ll never be able to fully repay the debt I owe to it. 2/
nature.com/articles/nrd32…

Time for another PK tweetorial, this time about the oft-misunderstood distinction between oral absorption and oral bioavailability. These are not the same thing, with different meanings and different implications for medicinal chemistry. 1/ Warning for the math-phobic: this topic does require a smidge of math to understand, but nothing beyond basic high school algebra. Not too scary, promise. 😱2/